The intersection between DNA damage response and cell death pathways

The intersection between DNA damage response and cell death pathways

Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between th...

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Дата:2012
Автори: Nowsheen, S., Yang, E.S.
Формат: Стаття
Мова:English
Опубліковано: Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України 2012
Назва видання:Experimental Oncology
Теми:
Reviews
Онлайн доступ:http://dspace.nbuv.gov.ua/handle/123456789/139048
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Цитувати:The intersection between DNA damage response and cell death pathways / S. Howsheen, E.S. Yang // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 243-254. — Бібліогр.: 128 назв. — англ.

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Digital Library of Periodicals of National Academy of Sciences of Ukraine
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spelling irk-123456789-1390482018-06-20T03:06:01Z The intersection between DNA damage response and cell death pathways Nowsheen, S. Yang, E.S. Reviews Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etiology of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. 2012 Article The intersection between DNA damage response and cell death pathways / S. Howsheen, E.S. Yang // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 243-254. — Бібліогр.: 128 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/139048 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
topic Reviews
Reviews
spellingShingle Reviews
Reviews
Nowsheen, S.
Yang, E.S.
The intersection between DNA damage response and cell death pathways
Experimental Oncology
description Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etiology of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
format Article
author Nowsheen, S.
Yang, E.S.
author_facet Nowsheen, S.
Yang, E.S.
author_sort Nowsheen, S.
title The intersection between DNA damage response and cell death pathways
title_short The intersection between DNA damage response and cell death pathways
title_full The intersection between DNA damage response and cell death pathways
title_fullStr The intersection between DNA damage response and cell death pathways
title_full_unstemmed The intersection between DNA damage response and cell death pathways
title_sort intersection between dna damage response and cell death pathways
publisher Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
publishDate 2012
topic_facet Reviews
url http://dspace.nbuv.gov.ua/handle/123456789/139048
citation_txt The intersection between DNA damage response and cell death pathways / S. Howsheen, E.S. Yang // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 243-254. — Бібліогр.: 128 назв. — англ.
series Experimental Oncology
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AT yanges intersectionbetweendnadamageresponseandcelldeathpathways
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fulltext Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��� THE INTERSECTION BETWEEN DNA DAMAGE RESPONSE AND CELL DEATH PATHWAYS S. Nowsheen1, E.S. Yang1,2,3,* Departments of 1Radiation Oncology, 2Cell, Developmental, and Integrative Biology, and 3Pharmacology and Toxicology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Alabama, USA Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etio­ logy of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. Key Words: poly(ADP­ribose) polymerase, EGFR, GSK3, BRCA1, apoptosis, p53, DNA damage and repair, balance between cell survival and death. Cell death is a fundamental cellular response that has a pivotal role in development as well as maintain- ing tissue homeostasis �y eliminating unwanted cells. It is composed of �oth controlled and uncontrolled mechanisms� including apoptosis� autophagy� and necrosis. Apoptosis is a regulated cell death process that reflects the cellular decision to die in response to cues from the environment and is executed �y in- trinsic cellular machinery [�� �]. In contrast� necrosis is uncontrolled cell death �rought upon �y overwhelm- ing stress. Lastly� autophagy is characterized �y self- destruction starting with engulfment of cytoplasmic material �y the phagophore and sequestration of ma- terial to the autophagic vacuoles� where they are even- tually destroyed [�]. The type and strength of stimuli� tissue type� developmental stage of the tissue� and the physiologic cellular microenvironment determines which cell death process is undertaken [�]. The human �ody is continuously exposed to vari- ous external and internal stresses� such as hypoxia� toxins� oxidative stress� and many others [����]. The a�ility of individual cells to adapt to these stresses is crucial for their survival. Alternatively� if too much damage has �een sustained� coordinated activation of cell death processes must occur to rid the �ody of cells that contain potential disease initiating muta- tions. Thus� complex adaptation strategies such as cell cycle checkpoints� DNA damage response pathways� and programmed cell death have evolved to com�at these environmental and physiological threats [�]. In this review� we will focus on one of these stresses� DNA damage� as it relates to the cell death processes. Ultimately� im�alance �etween DNA damage/repair and activation/inactivation of these cell death pro- cesses leads to carcinogenesis and may even alter tumor response to therapy. APOPTOSIS Apoptosis is a vital process of programmed cell death characterized �y distinct morphological characteristics and energy-dependent �iochemical mechanisms [�� �]. It is an integral component of vari- ous homeostatic and defense processes including normal cell turnover� aging� proper development and functioning of the immune system� hormone dependent atrophy� em�ryonic development� and chemical-induced cell death [�]. Either too much or too little apoptosis leads to various disease condi- tions including autoimmune and neurodegenerative disorders� ischemic damage� and cancer [�� 9���]. Thus� the a�ility to modulate the life and death of a cell has immense therapeutic potential and has �een the su�ject of intense research over the years. Apoptosis ultimately leads to a series of coordi- nated and energy-dependent activation of a group of cysteine proteases — caspases [�� ����8]. This Received: June 22, 2012. *Correspondence: Fax: 205-975-0784 E-mail: eyang@uab.edu Abbreviations used: 8-OHdG — 8-hydroxydeoxyguanosine; AP — apu- rinic/apyrimidinic; APAF-1 — apoptotic protease activating factor-1; ATM — ataxia telangiectasia mutated; ATR — ataxia telangiectasia and Rad3 related; BARD — BRCA1-associated RING domain protein; BER — base excision repair; BRCT — BRCA1 C-terminus; CDK — cy- clin dependent kinase; CREB — cyclic AMP response element binding protein; DD — death domain; DED — death effector domain; DISC — death inducing signaling complex; DNA PK — DNA-dependent protein kinase; DSB — double strand break; EGFR — epidermal growth factor receptor; FADD — Fas-associated death domain protein; FOXO — Forkhead box class O; GSK3 — glycogen synthase kinase 3; HR — ho- mologous recombination; HSF-1 — heat shock factor-1; MMR — mis- match repair; MRN — Mre11–Rad50–Nbs1; NEMO — NF-κB essential modulator; NER — nucleotide excision repair; NF-κB — nuclear factor- κB, NHEJ — non-homologous end joining, PAR — poly(ADP-ribose), PARP — poly(ADP-ribose) polymerase; PARylation — poly(ADP- ribosyl)ation; PUMA — p53 upregulated modulator of apoptosis; RIP1 — receptor-interacting protein 1; RPA — replication protein A; SIRT — sirtuins; SSB — single strand break; SUMO — small ubiquitin- like modifier; TNFR — tumor necrosis factor receptor; TRADD — tumor necrosis factor receptor type 1-associated DEATH domain. Exp Oncol ���� ��� �� ������� INVITED REVIEW ��� Experimental Oncology ��� �������� ���� ��eptem�er� leads to a cascade of events that link the initiating stimuli to cellular death �Fig. ��. Early apoptosis is cha- racterized �y cell shrinkage� dense cytoplasm� tightly packed organelles� and pyknosis due to chromatin condensation [�� ��� �8� �9]. This is followed �y �ud- ding which involves extensive plasma mem�rane �le�- �ing� karyorrhexis and separation of cell fragments into apoptotic �odies [�� �9]. The apoptotic �odies are su�sequently phagocytosed �y macrophages� parenchymal cells� or neoplastic cells and degraded within phagolysosomes [�� ��� �9]. �ince apoptotic cells do not release their cellular content into the interstitial tissue and there are no inflammatory cyto- kines produced� there are no inflammatory reactions associated with apoptosis [�� ��� �9]. The major apoptotic pathways include the extrinsic or death receptor pathway� the intrinsic or mitochon- drial pathway� and the perforin/granzyme pathway that involves T-cell mediated cytotoxicity �Fig. ��. For this review we will focus �riefly on the extrinsic and intrinsic pathways. For a more in depth discussion� please refer to these excellent reviews [�� �6]. Extrinsic pathway As mentioned a�ove� the extrinsic apoptotic signal- ing is mediated �y the activation of death receptors [�� ��� ��]. The death receptors are cell surface recep- tors that transmit apoptotic signals after �inding with specific activating ligands. Death receptors �elong to the tumor necrosis factor receptor �TNFR� gene superfamily� including TNFR-�� Fas/CD9�� and the TRAIL receptors DR-� and DR-�. They are characte- rized �y cysteine rich extracellular su�domains which allow highly specific ligand recognition� su�sequent trimerization� and activation of the death receptor [��]. �u�sequent signaling is mediated �y the cy- toplasmic part of the death receptor which contains a conserved sequence termed the death domain �DD�. Adapter molecules like Fas-associated death domain protein �FADD� or Tumor necrosis factor receptor type �-associated DEATH domain �TRADD� possess the same sequence which allows them to form the death inducing signaling complex �DI�C� and further propagate the signal [��� ��]. Another domain of the FADD� the death effector domain �DED�� sequesters procaspase-8 to the DI�C. Accumulation of procas- pase-8 at the DI�C leads to autocatalytic activation due to autopreoteolysis. This su�sequently releases active caspase-8 which activates effector caspases resulting in cell death [�� ��� ��]. Intrinsic pathway On the other hand� the intrinsic apoptosis pathways involve procaspase-9 which is activated downstream of mitochondrial proapoptotic events at the cytosolic death signaling protein complex� the apoptosome [�� ��]. Disruption of the inner mitochondrial transmem- �rane potential and permea�ility releases proapoptotic proteins from the mitochondrial intermem�rane space into the cytoplasm. The released proteins include Fig. 1. �ignaling events characteristic of apoptosis Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��� cytochrome c� which activates the apoptosome and therefore the caspase cascade [�� ��]. Dimerization of procaspase-9 molecules at the Apaf-� scaffold induces caspase-9 activation and su�sequent proteo- lytic activation of the effector procaspases-�� -6� and -7 [�� ��]. These cleave protein su�strates� including procaspases� resulting in the mediation and amplifica- tion of the death signal and eventually in the execution of cell death [�� ��]. There is significant crosstalk �etween the pathways and molecules in one pathway can influence the other [�� ��]. The pathways converge on the same execu- tion route which is initiated �y the cleavage of caspase � and results in DNA fragmentation� degradation of cytoskeletal and nuclear proteins� cross-linking of various proteins� formation of apoptotic �odies� expression of ligands for phagocytic cell receptors and phagocytosis [�]. Ultimately� activation of caspases leads to an irreversi�le cascade of events progressing towards cell death. As mentioned earlier� many cellular stresses can impact survival versus death pathways. In the next section� we focus on one particular cell stress� that is� DNA damage. THE DNA DAMAGE RESPONSE The human genome is under constant attack which leads to thousands of DNA lesions per day. The cellular response to DNA damage is critical for maintenance of genomic integrity [�� �� ��]. Dysregulation of this DNA damage response leads to genomic insta�ility� which can result in the inactivation of pro-apoptotic pathways and the survival of cells that are polyploid� contain damaged DNA� and have dysregulated telomere maintenance [�� �� ��� ��]. �uppression of the tightly regulated apoptotic process may thus play a critical role in the development of some cancers [�� �� 8� ��]. Com�ating this malignant transformation process is the DNA damage response� a complex mechanism to detect the a�ove mentioned lesions� signal their presence� and promote their repair. Additionally� mechanisms are in place such that if the damage is too great or repair is ineffective� activation of cell death pathways such as apoptosis or necrosis ensues �Fig. �� [�� 8� ��]. These steps are in place to com�at the threats posed �y excess or unrepaired DNA da- mage [�� 8� ��]. In this next section� we �riefly discuss the different types of DNA damage and the cellular responses to such damage to ultimately regulate cell fate. DNA can �e damaged �y exogenous agents such as radiation� x-ray� UV� alkylating agents� as well as �y the �y-products from endogenous processes such as reac- tive oxygen and nitrogen species from meta�olism and errors from DNA replication [��8� ��]. The resultant DNA damage either involves one or �oth strands of the DNA �single strand vs. dou�le strand �reaks� respec- tively�. While unresolved single strand �reaks ���Bs� can �e converted to dou�le strand �reaks �D�Bs� and repaired� unrepaired D�Bs can lead to severe conse- quences in cells. D�Bs can �e mutagenic� since they can potentially affect the expression of multiple genes. Most importantly� as little as one unrepaired D�B can �e lethal to the cell [��8� ��]. Fig. 2. The complex relationship �etween DNA damage� repair and apoptosis. DNA damage triggers cellular responses such as cell cycle arrest� post-translational protein modifications� DNA repair� and transcription of pro/anti survival genes. The �alance �etween these processes ultimately determines cell fate Exogenously� ultraviolet and other types of high en- ergy radiation can induce ��Bs and D�Bs. UV-induced damage can also result in the production of pyrimidine dimers� where covalent cross-links occur in cytosine and thymine residues� disrupting DNA polymerases and preventing DNA replication [��8]. Other agents can form DNA adducts and inter/intra strand crosslinks which� if left unrepaired� can lead to permanent mu- tations resulting in cell transformation and ultimately tumor development [��8]. Endogenously� oxidative DNA damage can occur and involves oxidation of specific �ases. 8-hydroxy- deoxyguanosine �8-OHdG� is the most common marker for oxidative DNA damage [��8]. Oxidative stress plays a central role in the pathophysiology of age-induced apoptosis via accumulated free radical-induced dam- age to the mitochondria. On the other hand� hydrolytic DNA damage involves deamination or the total removal of individual �ases. Loss of DNA �ases� known as AP �apurinic/apyrimidinic� sites� can �e particularly muta- genic and if left unrepaired they can inhi�it transcription [7� ��]. Interestingly� hydrolytic damage may result from the overa�undance of reactive oxygen species� often a �yproduct of respiration. Of course� the type and severity of damage to the DNA dictate the cellular response and ultimately cell fate [��]. Regardless of the type of DNA damage� the re- sponse to this insult involves sensing the damage� activating the checkpoints� and repairing/resolving the DNA lesions. These processes will �e discussed �elow. DNA damage sensors In order to initiate the DNA damage response� DNA damage sensors must first detect the a�errant DNA lesions. The Mre���Rad���N�s� �MRN� complex acts as the sensor of DNA damage and maintains genomic ��6 Experimental Oncology ��� �������� ���� ��eptem�er� sta�ility �y processing DNA ends and recruiting/�ridg- ing other mem�ers of the DNA damage response [�� ��� ��� �6��8]. �pecifically� Rad�� recognizes the DNA� N�s� recruits other DNA repair proteins to D�B lesions� and Mre�� processes the DNA ends with its DNA nuclease activity [�7]. This leads to activation of Ataxia Telangiectasia Mutated �ATM� or Ataxia Telan- giectasia and Rad� Related �ATR� depending on where the damage resides �ATM: DNA D�Bs on chromatin vs. ATR: stalled replication forks� [�6� �9� ��]. It is at this point where a cascade of signaling events is orches- trated to activate checkpoints and assem�le the re- maining mem�ers of the DNA repair complex. Checkpoint activation Upon sensing the DNA damage� a coordinated activation of DNA damage checkpoints as well as DNA repair proteins is required to arrest the cell cycle� thus allowing time for repair processes [��]. Checkpoints also induce changes in telomeric chromatin and recruitment of DNA repair proteins to sites of DNA damage� activation of transcription� telomere length� and induction of cell death �y apoptosis [��]. Not surprisingly� several checkpoint genes are essential for cell and organism survival. Chk�� a serine/threonine-protein kinase is required for checkpoint-mediated cell cycle arrest and activa- tion of DNA repair in response to the presence of DNA damage or unreplicated DNA. Chk� �inds to and phosphorylates CDC�� which creates �inding sites for ��-�-� proteins and triggers degradation of CDC�� via u�iquitination pathway and proteosomal degradation [��� ��]. This leads to increased inhi�itory tyrosine phosphorylation of CDK-cyclin complexes and �locks cell cycle progression. Chk� also �inds to Rad�� which promotes the release of Rad�� from BRCA�� increas- ing the chromatin association of Rad�� and su�se- quent HR-mediated DNA repair [��]. Chk� also pro- motes repair of DNA cross-links �y phosphorylating FANCE which is required for the nuclear accumulation of FANCC and provides a critical �ridge �etween the FA complex and FANCD� [��]. Chk� also plays an essential role in maintenance of replication fork �y regulating PCNA [��]. Besides� it also plays a role �y modulating transcription of genes involved in cell- cycle progression through phosphorylation of his- tones and su�sequent epigenetic silencing of genes. Chk� phosphorylates R�� to promote its interaction with the E�F family of transcription factors trigger- ing su�sequent cell cycle arrest and phosphorylates p�� activating the protein and promoting cell cycle arrest as well [��� ��]. Chk� functions similar to Chk�� regulating cell cycle checkpoint arrest through phosphorylation of CDC��� inhi�iting their activity [��� ����7]. In- hi�ition of CDC�� phosphatase activity leads to in- creased inhi�itory tyrosine phosphorylation of CDK- cyclin complexes and �locks cell cycle progression. Chk� also phosphorylates NEK6 which is involved in G�/M cell cycle arrest [��]. �imilar to Chk�� Chk� regulates HR-mediated DNA repair through phosphorylation of BRCA�� enhancing the chromatin association of RAD��. Moreover� Chk� promotes the transcription of genes involved in DNA repair �including BRCA�� through the phosphorylation and activation of the transcription factor FOXM� [��]. Chk� also regulates apoptosis through the phosphorylation of p��� MDM� and PML [��� �6� �8]. Chk� mediated phosphorylation of p�� reverses inhi�ition �y MDM�� leading to accumulation of active p��. Chk� depen- dent phosphorylation of MDM� also functions to re- duce degradation of p��. The kinase also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E�F�. Fi- nally� Chk� has a tumor suppressor role as well in that it functions in mitotic spindle assem�ly �y phosphory- lating BRCA� and a�sence of Chk� has �een o�served in some cancers [��� ����8]. Cyclin dependent kinase �CDK� family of serine/ threonine kinases regulate cell cycle progression through phosphorylation of proteins that function at specific phases of the cell cycle [�6� �9]. Differ- ent CDKs act at different phases of the cell cycle and their activity is each dependent on association with a mem�er of the cyclin family of proteins. Cdk�-cyclin B is important for the M phase transition while Cdk�- cyclin E association is critical for G�/� transition. Cdk�-cyclin E also functions in the � and G� phases while CDK�-cyclin E and CDK6-cyclin D control progression through the G� phase of the cell cycle �y phosphorylation of the tumor suppressor protein� R� [�6� �9]. These proteins have thus �een actively studied for cancer therapy. DNA repair pathways Once the DNA damage has �een sensed and checkpoints activated� the process of repairing this damage is initiated. We will first focus on the D�B repair pathways� of which there are � major path- ways: the homologous recom�ination �HR� and non-homologous end joining �NHEJ� [6�8� ��� ��]. HR relies on the presence of a sister chromatid and the cell cycle-regulated �`-to-�` resection of DNA ends that generates stretches of single stranded DNA. This single stranded DNA is �ound �y replication protein A �RPA�. BRCA� su�sequently �inds Rad�� and pro- motes its loading onto RPA coated single stranded DNA to produce a RAD��-single stranded DNA nu- cleoprotein filament. RPA-coated ssDNA also leads to recruitment and activation of the checkpoint kinase ATR� which phosphorylates various targets� includ- ing the downstream checkpoint kinase CHK�. This cascade of events promotes DNA strand invasion and su�sequent HR events. Because of the use of the ho- mologous sister chromatid as template� HR is an error free repair pathway and the major mechanism utilized �y cells for repairing D�Bs and restarting stalled rep- lication forks [8� �6]. On the contrary� the error-prone NHEJ involves connecting and resealing the two ends of DNA D�B without the need for sequence homology �etween the ends. Thus� this process is not dependent on the cell Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��7 cycle and is� in fact� active throughout all phases of the cell cycle. It involves among others� Ku 7�/8�� DNA protein kinase family of proteins [8� ��� ��]. It is not yet clear what dictates the choice of repair pathway. Research suggests that the choice �etween NHEJ or HR pathways depends on cell cycle stage; NHEJ is active throughout the cell cycle� and its activity increases as cells progress from G� to G�/M �G� < � < G�/M�. HR is nearly a�sent in G�� most active in the � phase� and declines in G�/M [7� 8� ��� ��]. The over- all efficiency of NHEJ is higher than HR at all cell cycle stages. Cells usually utilize error-prone NHEJ as the major D�B repair pathway at all cell cycle stages� while HR is used primarily in the � phase. Reports also sug- gest key repair players such as CtIP� BRCA�� Ku� and others to impact the choice of D�B repair �y control- ling the initial events of D�B repair such as D�B end processing/resection [�����]. For ��Bs� different repair processes are utilized. Usually� the intact complementary strand can �e used as a template to repair the damaged strand via a variety of repair mechanisms like �ase excision repair �BER� to repair damage to a single �ase caused �y oxida- tion� alkylation� hydrolysis� or deamination� nucleotide excision repair �NER� to repair �ulky� helix-distorting lesions such as pyrimidine dimers and photo-adducts� and mismatch repair �MMR� to corrects errors of DNA replication and recom�ination which may have resulted in mispaired ��ut undamaged� nucleotides [�� 7� 8� ��]. Formation of ��Bs is closely linked to damaged �ases and their attempted repair. It is worth noting that D�Bs may form during the attempted repair of ��Bs [�� 7� 8� ��]. Interestingly� the chromatin structure may �e modulated to facilitate protein recruitment during repair [��]. Modifications of DNA-associated histone proteins maintain genomic sta�ility. Upon the induction of DNA damage� phosphorylation of histones dictates if repair is justified or apoptosis is warranted [��� �6]. It is truly amazing how a cell decides whether to pursue repair and when to a�ort repair to favor apoptosis. In this next section� we will discuss various key players in the DNA damage response who also play vital roles in regulating apoptosis. INTERSECTION BETWEEN DNA DAMAGE RESPONSE AND APOPTOSIS DNA damage sustained from normal DNA repli- cation/cell processes� stress� mitotic catastrophe� agents such as radiation� toxins� hormones� growth factors� cytokines� and drugs� and reactive oxygen species can induce apoptosis if left unrepaired [�� �� 7� 8� ��]. Additionally� current DNA damaging agents used in therapies act to overwhelm cellular DNA repair capacity to activate cell death processes. For example� irradiation� a standard treatment modality for a num�er of cancers such as �rain� �reast� and prostate� as well as a variety of chemotherapeutic agents induce DNA damage leading to apoptosis [�� �� 7� 8� ��� �7]. Below� we will discuss several key players that intersect the DNA repair pathways with apoptotic pathways. P53 and apoptosis The tumor suppressor protein p�� has �een shown to mediate cellular stress responses in that p�� can initiate DNA repair� cell-cycle arrest� senescence and� importantly� apoptosis [��� �6� �8� ��� �8���]. These responses suppress tumor formation. Thus� it is not surprising that most tumors have p�� mutations [��]. p�� mediates DNA damage response �y stimulating the nuclear release of histone H�. Phosphorylation is one of the primary post-translational modifications of p�� and this increases its sta�ility. Various kinases such as ATM� Chk� and Chk� are responsi�le for the phosphorylation of p��. Other post-translational modi- fications such as acetylation� u�iquitination� methy- lation� sumoylation� and neddylation also regulates p�� protein sta�ility and transcriptional activation [�6� �8� ��� �8� ��� ��]. The E� u�iquitin ligase MDM� regu- lates p�� activity �y �inding to its N-terminal transac- tivation domain� thus preventing its interaction with other transcriptional factors. MDM� also induces nuclear export of p�� and targets it for proteasomal degradation [�6� �8� ��� �8� ��� ��]. In event of failed DNA repair p�� initiates apoptosis �y transactivating pro-apoptotic proteins such as BAX� BID� PUMA and NOXA which permea�ilizes the mitochondrial mem- �rane and leaks the pro-apoptotic factors [�6� �8� ��� �8� ��� ��]. p�� stimulates the extrinsic and/or the intrinsic pathway depending on the DNA damage. p�� has �een reported to �ind to the outer mitochon- drial mem�rane and antagonize the anti-apoptotic function of BCL� and BCL-XL. p�� represses the activity of BCL�� an anti-apoptotic protein involved in retaining the mitochondrial permea�ility� as well as survivin. Moreover� p�� also initiates apoptosis via proteins localized on the endoplasmic reticulum and plasma mem�rane such as DR�. p�� can also exert transcription independent effects on mitochondria mem�rane permea�ility �y activating the pro-apop- totic protein BAX or �y neutralizing the anti-apoptotic proteins BCL� or BCL-XL [��� �6� �8� ��� �8� ��� ��]. Tumor cells possessing wild type p�� undergo apoptosis to a greater extent following DNA damage than cells that possess mutations in p��. DNA damage can also activate p��-independent apoptosis which may �e called upon especially in cases in which p�� are mutated. The p�� homologs p6� and p7� are involved in this response. Unlike mutations in p��� mutations in p7� do not predispose to tumor formation �ut do have an impact on the DNA damage response. p7� is also often overexpressed in cancer. As mentioned a�ove� in response to DNA lesions� ATM and/or ATR activate CHK� and CHK�� which in turn activate E�F� [�8]. This in turn stimulates transcription of the p7� gene� increas- ing the levels of p7� protein. While p�� requires p6� and p7� to activate apoptosis� p7� is pro-apoptotic even in the a�sence of p��. p7�-induced apoptosis is me- diated �y transcriptional upregulation of PUMA� which in turn induces mitochondrial translocation of BAX and cytochrome c release �discussed a�ove�. p7� also in- duces mitochondrial dysfunction via NOXA. On the other ��8 Experimental Oncology ��� �������� ���� ��eptem�er� hand� p6� has the a�ility to suppress p7�-mediated apoptosis [��� �6� �8� ��� �8� ��� ��]. Nuclear factor-κB �NF-κB� also has a role in p��- independent apoptosis. This transcription factor is gen- erally anti-apoptotic and promotes survival. Activation of NF-κB in response to DNA damage is mediated �y �UMOylation and ATM-dependent phosphorylation of NEMO �NF-κB essential modulator�. Under some circumstances� however� NF-κB exhi�its pro-apoptotic activity. For instance� presence of excess reactive oxygen species can induce NFκB-mediated transcription of the FA� ligand� there�y stimulating apoptosis [��]. NF-κB in- duces TNF-α production and su�sequent receptor-inter- acting protein � �RIP�� autophosphorylation. In associa- tion with NEMO� RIP� kinase promotes JNK�-mediated induction of IL-8 and recruits FADD to activate caspase 8 which then induces apoptosis [��]. p��-independent apoptosis can also �e triggered �y BCL-� degradation and G�K� which is detailed in a later section [��]. BRCA1 and apoptosis The tumor suppressor BRCA� plays an integral role in the maintenance of genomic sta�ility and modulates cellular response to DNA damage [�6��8]. It is involved in �oth the major DNA dou�le strand �reak repair pathways — HR and NHEJ [�6]. BRCA� func- tions in a variety of cellular processes including chro- matin remodeling� protein u�iquitination� DNA rep- lication� DNA repair� regulation of transcription� cell cycle checkpoint control� and apoptosis [�6��8]. BRCA� function is regulated through diverse mecha- nisms including transcription control� protein-protein interaction� and post-translational modification [�9� �6� �8� �9]. BRCA� is a nuclear-cytoplasmic shuttling protein and its function may �e regulated via active shuttling �etween the cellular compartments [�9� �6� �8� �9]. When nuclear� BRCA� controls high fidelity repair of damaged DNA. In contrast� BRCA� has �een shown to enhance p��-independent apoptosis when cytoplasmic [�9� �6� �8� �9]. BRCA� contains two nu- clear localization signals which target it to the nucleus via importin and two nuclear export sequences which transport it to the cytoplasm via the CRM�/exportin pathway [�9� �6� �8�6�]. As mentioned a�ove� BRCA� shuttling can also �e regulated via protein-protein interaction. The BRCA�-associated RING domain protein �BARD�� has �een shown to prevent CRM� dependent nuclear export of BRCA� �y �inding to and masking the BRCA� NE� located at the N-terminal RING domain. On the contrary� the BRCA� C-terminus �BRCT� do- main has �een shown to play a crucial role in DNA damage-induced nuclear import of BRCA� through association with numerous other proteins� including p��� CtIP and BACH [��� �9� �6� 6�]. p�� seems to �e an important player in DNA damage induced BRCA� nuclear export since human �reast cancer cells with deficiency in p�� function exhi�it a�er- rant BRCA� shuttling [�9]. Mutations that target the BRCT region of BRCA� have �een shown to exclude BRCA� from the nucleus �y �locking nuclear import. Thus� the critical region responsi�le for regulating the location of BRCA� appears to reside in the BRCT domain. Nuclear exclusion of BRCA� can �e thera- peutically exploited with poly�ADP-ri�ose� polymerase �PARP� inhi�itors as well as other DNA damaging agents such as cisplatin [�9]. In addition to the repair of damaged DNA� BRCA� plays a role in apoptosis [6��6�]. �pecifically� overexpression of BRCA� induces apoptosis and the process has �een linked to DNA damage-induced BRCA� nuclear export and the c-Jun N-terminal ki- nase pathway [6�]. BARD�� which �inds and masks the BRCA� nuclear export sequence to prevent BRCA� nuclear export� inhi�its this BRCA�-mediated apoptosis. Moreover� the apoptotic pathway stimu- lated �y BRCA� is independent of p�� [�6� �9]. BRCA� has also �een reported to �e present in the mitochondria where it promotes BCL� mediated apoptosis. BCL�-mediated targeting of BRCA� to the endomem�ranes depletes BRCA� from the nucleus resulting in decreased HR-mediated repair [66� 67]. In addition� BCL� expression is low in BRCA�-asso- ciated tumors [68]. DNA-dependent protein kinase (DNA PK) and apoptosis The DNA-dependent protein kinase �DNA PK� plays a critical role in D�B repair and V�D�J recom�ination [69]. DNA PK plays a central role in the NHEJ pathway for D�B repair in mammalian cells via autophosphory- lation events as well as its association with other DNA repair proteins such as BRCA� and Ku. Ku �inds to the DNA end and recruits DNA PK� sta�ilizing its �inding to DNA. This is followed �y �ridging of the �roken ends �y DNA PK to facilitate rejoining. DNA-PK also recruits and activates proteins involved in DNA end-processing and ligation. The coordinated assem�ly of Ku and DNA-PKcs on DNA ends is followed �y recruitment of the DNA ligase IV�XRCC� complex that is respon- si�le for the rejoining step [�� 7� 8� ��� 69]. DNA PK is present at the telomere and cap chromo- some ends� protecting them telomere and preventing chromosome end-to-end fusions. This interaction with telomerase helps to maintain telomere length as well [7�]. Recently� it was reported that poly�ADP-ri�ose� polymerase � �PARP�� interacts genetically with the DNA PK catalytic su�unit to prevent cancer �lympho- ma� �y suppressing p�� mutation and telomere fusions [7�]. The role of PARP in DNA repair and apoptosis is discussed in a su�sequent section. DNA PK also plays a crucial role in triggering apop- tosis in response to severe DNA damage or critically shortened telomeres [7�� 7�� 7�]. The a�ility to trigger apoptosis in the presence of unresolved DNA dam- age is critical for preventing progression to cancer. In response to DNA damage� DNA PK phosphorylates p�� and triggers p��-dependent apoptosis. Converse- ly� DNA PK undergoes proteasomal degradation later on in the apoptotic process which aids to suppress pro- survival signals [7�]. The Ku7� su�unit of DNA-PK has �een shown to suppress apoptosis �y sequestering Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��9 Bax from mitochondria [7�]. Increased acetylation of cytoplasmic Ku7� disrupts the Ku7�-Bax interaction augmenting apoptosis [7�]. PARP and apoptosis PARP is a family of proteins involved in a num- �er of cellular processes including DNA repair and apoptosis [76]. PARP is predominantly located in the nucleus where it promotes BER-mediated DNA single strand �reak repair �y �inding to the DNA and induc- ing a structural modification [77]. It also induces the synthesis of poly�ADP-ri�ose� �PAR� chains which acts as a signal for other DNA repair proteins. An early transient �urst of poly�ADP-ri�osyl�ation �PARylation� of nuclear proteins followed �y caspase-� mediated cleavage of PARP is required for apoptosis to pro- ceed [8� 76�8�]. This inactivation of PARP prevents depletion of NAD �a PARP su�strate� and ATP� which are required for later events in apoptosis. PARylation plays diverse roles in many molecular and cellular processes� including DNA damage detection and repair� chromatin modification� transcription� cell death pathways� and mitotic apparatus function [76� 77� 79�8�]. These processes are critical for genome maintenance� carcinogenesis� aging� inflammation� and neuronal function [8� 76�8�]. PARP-� interacts physically and functionally with various proteins involved in these DNA repair path- ways� and recruits the repair proteins to sites of DNA damage such as XRCC-� in BER and DNA PK in NHEJ- mediated repair. PAR� as covalent attachment of au- tomodified PARP-� and PARP-�� acts to recruit repair proteins to sites of DNA damage [8� 7�� 76�78� 8�� 8�]. PARP dependent ��B repair and BRCA�- and BRCA�-dependent D�B repair has �een exploited for cancer therapy [6�8� 78� 8�]. As mentioned a�ove� BRCA� and BRCA� are tumor-suppressor proteins important for D�B repair �y HR� and mutation of the genes encoding these proteins causes predisposition to �reast and ovarian cancers. PARP inhi�itors have shown promising results in BRCA deficient tumors and other DNA repair deficient tumors in clinical trials when com�ined with other cytotoxic agents [8��87]. We and others have recently reported that the PARP inhi�ition induces apoptosis in a variety of cell types. We have shown that in conjunction with EGFR inhi�i- tors� the PARP inhi�itor ABT-888 activates the intrinsic apoptotic pathway as evidenced �y cleavage of caspase � and 9 [78]. PARP inhi�itor treatment also induces phosphorylation of DNA PK and stimulates error-prone NHEJ-mediated repair in HR-deficient cells� resulting in cell death. PARP� catalytic activity possi�ly regulates NHEJ in the a�sence of HR and thus� deregulated NHEJ may explain the exquisite cytotoxicity of HR deficient cells to PARP inhi�itors [78� 88]. PARP� inhi�itor induces caspase-independent cell death as well. It causes mitochondrial depolarization� mitochondrial permea�ility transition and mitochon- drial release of AIF which� upon release from the mitochondria� translocates into the nucleus� where it triggers nuclear DNA fragmentation [89� 9�]. Thus� PARP inhi�itors tilt cell death from necrosis to apop- tosis in cancer cells [9�]. ATM/ATR and apoptosis Defects in ATM are associated with cancers such as T-cell pro-lymphocytic leukemia� and B-cell chronic lymphocytic leukemia [6�8� 9�]. Defective ATM also predisposes to sporadic colon cancer in tumors with microsatellite insta�ility [9�]. Loss of ATM results in hypersensitivity to radiation and defect in cell cycle arrest [9�]. ATM is also involved in p7� mediated apoptosis [9�]. Radiation induces ATM-dependent c-A�l phosphorylation which then activates p7�. Upon commitment to apoptosis� caspases �cysteine aspartic acid proteases� are activated in a proteolytic cascade and ATM is cleaved �y a caspase-�-like apoptotic pro- tease. This generates a truncated ATM protein devoid of kinase activity �ut still retaining its DNA �inding a�ility. This functions to prevent further DNA repair and propagation of DNA damage signaling [9�� 9�]. As mentioned �efore� ATR activates p�� in response to DNA damage �y phosphorylating p�� [�9� ��� �6� ��]. In response to DNA damage� ATR also phosphory- lates and activates Chk�� which in turn phosphorylates p�� and regulates cell cycle progression. ATR also mediates phosphorylation of BRCA� in response to UV [�9� ��� �6� ��]. Thus� these signaling pathways can converge on �oth p�� and BRCA� mediated apoptosis. ATM/ATR also mediates BID phosphorylation� which is required for DNA damage-induced intra- � phase checkpoint [96]. An intact BH� domain is re- quired for apoptosis �ut not BID-mediated � phase effects. Thus the two functions may �e distinct. BID accumulates in �oth the nucleus and mitochondria following stress suggesting a possi�le role in DNA damage response. Furthermore� like ATM and ATR� BID localizes to the chromatin fraction of the nucleus following treatment with DNA-damaging agents [96]. Sirtuins (SIRT) and apoptosis �irtuins ��IRT� are a family of histone deacetylases which also has a role in the maintenance of genomic sta�ility [97]. They also possess mono-ri�osyltransferase activity [97� 98]. �IRT have �een implicated in influencing aging and regulating transcription� apoptosis and stress resistance [99]. For instance� �IRT� can deacetylate vari- ous factors linked to the repair of DNA damage� includ- ing the Werner helicase and NB�� [�������]. A�sence of �IRT results in increased chromosomal a�errations and impaired DNA repair. In addition �IRTs are recruited to sites of DNA �reaks following DNA damage to avoid genomic insta�ility [���]. Thus� �IRTs regulate epigenetic silencing and chromatin modification. �IRT�� the human �ir� homolog� acts as a negative regulator of the transactivation function of p�� �y �ind- ing and deacetylating p��� there�y repressing apop- tosis induced �y DNA damage [���� ���]. Persistent lesions keep PARP in an activated state and the nicotinamide produced �y the process inhi�its �IRT�. This leads to hyperacetylation and enhanced trans- activation of p�� which in turn leads to increase in the transcription of pro-apoptotic genes and su�sequent ��� Experimental Oncology ��� �������� ���� ��eptem�er� apoptosis. Besides p��� �IRT� can regulate other targets linked to cell death� including Ku7�� E�F� and TGF-β signaling [��6� ��7]. Another �IRT-mediated pro-survival pathway in- volves the Forkhead �ox class O �FOXO� transcription factors which control the expression of genes involved in apoptosis such as Fas ligand� Bim� TRAIL� cyclin D� Gadd��� p�7/Kip�� Gadd��� Mn�OD. Akt phosphory- lates FOXO factors in the presence of growth factors [��8� ��9]. This prevents their nuclear translocation. However� when the growth factor signaling is switched off� FOXOs are located in the nuclei and act as tran- scription factors. Acetyltransferases� PCAF and p���/ CBP mediated acetylation silences the transcription factors. The transcriptional activity of FOXO� is re- stored �y deacetylation carried out �y �IRT� which leads to resumption of gene transcription including DNA damage checkpoint genes. This increases the a�ility of FOXO to induce cell cycle arrest and resist oxi- dative stress [97�99� ��6���9]. Thus �IRT promotes cell survival via transcriptional regulation. Moreover� the concerted action of �IRT� and �IRT� appear to inhi�it cell death �y maintaining mitochondrial NAD levels following stress [98� ���]. It should �e noted that although �IRT predominantly antagonize stress- induced cell death pathways� �IRT� can also deacety- late components of the NFκB complex� leading to in- creased cell death� primarily senescence [98� ���]. Epidermal growth factor receptor (EGFR) and apoptosis The epidermal growth factor receptor �EGFR� plays an important role in the development and progres- sion of solid tumors. In addition� EGFR activation also mediates resistance to chemotherapy and radiation therapy [78� 88]. EGFR inhi�ition down-modulates survival pathways and shifts towards the proapoptotic Bcl-� expression and/or activation [���]. There are multiple inhi�itors of EGFR that are currently either used as a standard of care or are in clinical trials. Inhi�itors of the tyrosine kinase activity of EGFR compete with ATP for �inding to the tyrosine kinase pocket of the receptor. They have significant antitumor activity since the EGFR-TKIs �lock signaling �y �oth ERK and AKT pathways and induce apoptosis [���]. EGFR mediated apoptosis requires an active kinase �ut not EGFR auto- phosphorylation sites� meaning the truncated receptor can generate the apoptotic signal. EGFR can activate Ras and the induction in apoptosis is due to impaired Akt activation. EGFR inhi�ition induces BIM expression via inhi�ition of the MEK-ERK pathway and BIM induc- tion plays a key role in EGFR-TKI-induced apoptosis. Research suggests that �oth the PI�K-AKT-survivin and MEK-ERK-BIM pathways contri�ute independently to EGFR inhi�itor-induced apoptosis [������6]. The BH�-only protein PUMA �p�� upregulated modulator of apoptosis� plays an essential role in p��- dependent and -independent apoptosis. PUMA medi- ates apoptosis through the Bcl-� family proteins Bax/ Bak and the mitochondrial pathway [��7]. PUMA is also induced �y EGFR inhi�itors independent of p��. EGFR inhi�itors �lock phosphorylation of EGFR and inhi�it the PI�K/AKT pathway� which leads to increased expres- sion of p7� and its �inding to the PUMA promoter and su�sequent transactivation [��8]. Thus� PUMA func- tions as a critical mediator of EGFR inhi�itor-induced apoptosis� especially in head and neck cancer cells where EGFR inhi�itors are widely used. Moreover� p7�� p6�� and the PI�K/AKT pathway serve as key regulators of PUMA induction after EGFR inhi�ition [��9]. Recent evidence also suggests a key role of EGFR in �oth major DNA D�B repair pathways. �pecifically� EGFR �inds and activates DNA PK for NHEJ [���� ���]. Additionally� EGFR inhi�itors have �een shown to attenuate DNA repair pathways. Interestingly� we recently reported that the EGFR inhi�itor cetux- ima� reduced �oth NHEJ and HR in head and neck cancer cells and su�sequently induced a synthetic lethality with the PARP inhi�itor ABT-888 [78]. This enhanced cytotoxicity was associated with activation of the intrinsic apoptotic pathway [78]. This �rings forth the possi�ility that other DNA repair proteins may �e involved in the apoptotic response. We are actively investigating this avenue. Glycogen synthase kinase 3 (GSK3) and apop- tosis Another important player in linking extracellular sig- nals to DNA damage/repair and ultimately apoptosis is the glycogen synthase kinase � �G�K��. Phosphory- lation of su�strates �y G�K� allows it to modulate key processes including cell structure� meta�olism� gene expression and apoptosis [���]. G�K� has the unique capacity to either increase or decrease the apoptotic threshold due to its opposing regulation of the two major apoptotic signaling pathways. G�K� promotes cell death caused �y the mitochondrial intrinsic apoptotic pathway� �ut inhi�its the death receptor- mediated extrinsic apoptotic signaling pathway [���]. G�K� is involved in the apoptotic response following growth factor withdrawal� inhi�ition of the PI�K/Akt signaling pathway� DNA damage� ER stress� hypoxia/ ischemia� and oxidative stress [���]. Intrinsic apop- totic signaling which is activated �y cell damage is promoted �y G�K� �y facilitation of signals that cause disruption of mitochondria and �y regulation of transcription factors that control the expression of anti- or pro-apoptotic proteins. These transcription factors include p�� which was discussed a�ove and cyclic AMP response element �inding protein �CREB� [���� ���]. G�K�β activity in the nucleus promotes p��-induced expression of Bax in response to DNA damage and inhi�its CREB� which can �lock the CREB-dependent expression of the anti-apoptotic protein Bcl-� [���]. G�K� can regulate p�� levels through the phosphorylation of the p��-regulating protein MDM� as well as �y directly interacting with p�� [���]. G�K� promotes p��-mediated transcrip- tion of specific genes and regulates the intracellular localization of p�� [���]. p�� is also a�le to activate apoptosis independently of its transcription function �y acting directly on mitochondrial proteins� and Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��� G�K�β �inds p�� in the mitochondria� which may contri�ute to p��-induced apoptosis [��6]. In the canonical Wnt signaling pathway� the transcriptional co-activator β-catenin promotes growth and survival� �ut phosphorylation of β-catenin �y G�K� targets it for proteosomal degradation there�y promoting apopto- sis [���]. Activation of Wnt signaling inhi�its G�K� se- lectively in the Wnt signaling protein complex� causing accumulation of β-catenin and its translocation to the nucleus where it interacts with the TCF/LEF transcrip- tion factors to induce expression of pro-survival genes. G�K� phosphorylates heat shock factor-� �H�F-��� a pro-survival transcription factor to inhi�it its activity� there�y reducing expression of heat shock proteins� an action that can facilitate apoptosis [��7]. �ince G�K� is present in the mitochondria as well and there is a spike in G�K� levels following DNA damage� G�K� is uniquely positioned to regulate apoptosis. Pro-apoptotic mem�ers of the Bcl-� family of pro- teins such as Bax transmit the apoptotic signal to the mitochondria following phosphorylation �y G�K�. �tress such as DNA damage induces a conformational change in Bax that promotes its translocation from the cyto- plasm to the mitochondria where it can �oth sequester anti-apoptotic Bcl-� family proteins and oligomerize within the mitochondrial mem�rane. This as well as phos- phorlylation of the voltage-dependent anion channels �y G�K� disrupts the mitochondrial mem�rane potential and releases apoptotic proteins such as cytochrome c from the mitochondrial intermem�rane space into the cytoplasm. Cytochrome c in turn �inds to the protein apoptotic protease activating factor-� �APAF-��� ATP/ dATP� and procaspase-9 to form the apoptosome in the cytoplasm. This causes the activation of caspase-9� there�y triggering the activation of the caspase cascade as discussed a�ove [���� ���]. The extrinsic apoptotic pathway entails extracel- lular ligands stimulating cell-surface death receptors that initiate apoptosis �y activating caspase-8� and this early step in extrinsic apoptotic signaling is inhi�ited �y G�K�. Examples of death receptors include p��� Fas� DR� and DR�. Cellular insults induce recep- tor homo-trimerization followed �y the recruitment of cytoplasmic adaptor and effector proteins which activates the receptor. This complex su�sequently �inds to the cytoplasmic proteins FADD and procas- pase-8 �or procaspase-��� to form the DI�C. DI�C formation can allow autoactivation of caspase-8� which then leads to the activation of effector caspases� pri- marily caspases-�� -6� and -7 [���� ���]. This pathway is discussed in detail a�ove. Thus� G�K� modulates key steps in each of the two major pathways of apop- tosis� �ut in opposite directions. G�K�β knockout mice are em�ryonically lethal due to massive hepatocyte apoptosis� which demonstrates that G�K�β is an important inhi�itor of apoptosis [�7� ���� ��8]. G�K� inhi�itors promote apoptosis induced �y stimulation of DD-containing receptors �ut provide protection from many other insults that induce apoptosis. For instance� we have previously reported that inhi�ition of G�K� using lithium and other chemical inhi�itors se- lectively kill tumor cells such as gliomas and leukemia �ut protect normal tissues from radiation-induced toxicity. The mechanism involved enhanced NHEJ mediated D�B repair following IR in normal tissues �ut not cancer. �ince radiation cannot �e selectively delivered to cancer cells� it leads to many destructive cellular processes including apoptosis� genomic insta�ility� and autophagy. Cranial irradiation therapy is a standard method for treatment of �rain cancer �ut results in long term neurocognitive deficits� especially in children. Thus� treatment with G�K� inhi�itors may potentially improve the quality of life of cancer patients undergoing radiation treatment. �eve- ral clinical trials have �een initiated to test the efficacy of lithium in neuroprotection during the treatment of �rain tumors �ut the trials are still at their infancy [�7� ���� ��8]. It is perplexing that inhi�ition of G�K� upregulates DNA repair exclusively in normal cells. A possi�le explanation may �e that G�K� is already maximally inhi�ited in the majority of cancer. p�� status may also play a role in determining cellular response to G�K� inhi�ition �ut further research is warranted in this avenue. Our la� is currently investigating the role of G�K� in DNA damage/repair and how this relates to G�K�-induced neuroprotection. CONCLUSION A wide array of key players in the DNA damage re- sponse also is also involved in the interplay �etween cell survival and apoptosis. Further research is necessary to decipher the mechanisms �y which cell fate is de- termined. In this complex network� uncovering these mechanisms may allow for the understanding of certain diseases and the generation of more effective therapies. ACKNOWLEDGEMENT �ome of the work descri�ed in this review was supported �y the IMPACT Award from the Department of Radiation Oncology� University of Ala�ama-Birming- ham Comprehensive Cancer Center� a translational scholar award from the �idney Kimmel Foundation for cancer research� a pilot award from the Center for Clinical and Translational �cience �CCT�� and the Council of Center Directors �COCD� Translational Re- search Intramural Pilot Grant Program �grant num�er �UL� RR���777-��� from the NIH National Center for Research Resources� and a medical research award from the Ga�rielle’s Angel Foundation �to E�Y�. We recognize that we were una�le to cover all aspects of DNA damage response and cell death pathways in this review. 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