DNA Damage Response In Cancer Research Articles

Crosstalk between Wnt/β-catenin signaling pathway and DNA damage response in cancer: a new direction for overcoming therapy resistance.

Wnt signaling plays an important role in regulating the biological behavior of cancers, and many drugs targeting this signaling have been developed. Recently, a series of research have revealed that Wnt signaling could regulate DNA damage response (DDR) which is crucial for maintaining the genomic integrity in cells and closely related to cancer genome instability. Many drugs have been developed to target DNA damage response in cancers. Notably, different components of the Wnt and DDR pathways are involved in crosstalk, forming a complex regulatory network and providing new opportunities for cancer therapy. Here, we provide a brief overview of Wnt signaling and DDR in the field of cancer research and review the interactions between these two pathways. Finally, we also discuss the possibility of therapeutic agents targeting Wnt and DDR as potential cancer treatment strategies.

PD-1/PD-L1 and DNA Damage Response in Cancer.

The application of immunotherapy for cancer treatment is rapidly becoming more widespread. Immunotherapeutic agents are frequently combined with various types of treatments to obtain a more durable antitumor clinical response in patients who have developed resistance to monotherapy. Chemotherapeutic drugs that induce DNA damage and trigger DNA damage response (DDR) frequently induce an increase in the expression of the programmed death ligand-1 (PD-L1) that can be employed by cancer cells to avoid immune surveillance. PD-L1 exposed on cancer cells can in turn be targeted to re-establish the immune-reactive tumor microenvironment, which ultimately increases the tumor's susceptibility to combined therapies. Here we review the recent advances in how the DDR regulates PD-L1 expression and point out the effect of etoposide, irinotecan, and platinum compounds on the anti-tumor immune response.

Studying the Immunomodulatory Functions of PARP1 and PARP2 in Mouse Models of Cancer.

Poly-ADP-ribosylation of proteins, mediated by the two ADP-ribosyltransferases PARP1 and PARP2 in response to DNA damage, has emerged as a critical mediator of the DNA damage response (DDR). Accordingly, considering the critical role of DDR in cancer, PARP inhibitors (PARPi) have become an important class of therapeutics. PARPi have largely been considered for their intrinsic actions to tumor cells per se. However, these compounds also affect the immune response to tumors. It is now an emerging evidence supporting immunomodulatory roles of PARP1 and PARP2 which can facilitate or impede tumor progression. In this chapter, we describe some protocols to study the immunomodulatory functions of PARP1 and PARP2 in mouse tumor models.

Exploiting the DNA Damaging Activity of Liposomal Low Dose Cytarabine for Cancer Immunotherapy.

Perhaps the greatest limitation for the continually advancing developments in cancer immunotherapy remains the immunosuppressive tumor microenvironment (TME). The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis is an emerging immunotherapy target, with the resulting type I interferons and transcription factors acting at several levels in both tumor and immune cells for the generation of adaptive T cell responses. The cGAS-STING axis activation by therapeutic agents that induce DNA damage, such as certain chemotherapies, continues to be reported, highlighting the importance of the interplay of this signaling pathway and the DNA damage response in cancer immunity/immunotherapy. We have developed a multi-targeted mannosylated cationic liposomal immunomodulatory system (DS) which contains low doses of the chemotherapeutic cytarabine (Ara-C). In this work, we show that entrapment of non-cytotoxic doses of Ara-C within the DS improves its ability to induce DNA double strand breaks in human ovarian and colorectal cancer cell lines, as well as in various immune cells. Importantly, for the first time we demonstrate that the DNA damage induced by Ara-C/DS translates into cGAS-STING axis activation. We further demonstrate that Ara-C/DS-mediated DNA damage leads to upregulation of surface expression of immune ligands on cancer cells, coinciding with priming of cytotoxic lymphocytes as assessed using an ex vivo model of peripheral blood mononuclear cells from colorectal cancer patients, as well as an in vitro NK cell model. Overall, the results highlight a broad immunotherapeutic potential for Ara-C/DS by enhancing tumor-directed inflammatory responses.

DNA damage response signaling: A common link between cancer and cardiovascular diseases.

DNA damage response (DDR) signaling ensures genomic and proteomic homeostasis to maintain a healthy genome. Dysregulation either in the form of down- or upregulation in the DDR pathways correlates with various pathophysiological states, including cancer and cardiovascular diseases (CVDs). Impaired DDR is studied as a signature mechanism for cancer; however, it also plays a role in ischemia-reperfusion injury (IRI), inflammation, cardiovascular function, and aging, demonstrating a complex and intriguing relationship between cancer and pathophysiology of CVDs. Accordingly, there are increasing number of reports indicating higher incidences of CVDs in cancer patients. In the present review, we thoroughly discuss (1) different DDR pathways, (2) the functional cross talk among different DDR mechanisms, (3) the role of DDR in cancer, (4) the commonalities and differences of DDR between cancer and CVDs, (5) the role of DDR in pathophysiology of CVDs, (6) interventional strategies for targeting genomic instability in CVDs, and (7) future perspective.

The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response.

Ataxia telangiectasia and Rad-3 related kinase (ATR) signals DNA lesions and replication stress (RS) to the S and G2/M checkpoints and DNA repair pathways making it a promising target to exploit the dysregulated DNA damage response in cancer. ATR inhibitors (ATRi) are under clinical investigation as monotherapy and in combination with other anticancer agents. Molecular determinants of sensitivity to ATRi are common in ovarian cancer, suggesting the therapeutic potential of ATRi. We investigated the cytotoxicity of the ATRi, VE-821, in a panel of human ovarian cancer cell lines. High grade serous (HGS) cell lines were significantly more sensitive to VE-821 than non-HGS (p ≤ 0.0001) but previously identified determinants of sensitivity (TP53, ATM and BRCA1) were not predictive. Only low RAD51 (p = 0.041), TopBP1 (p = 0.026) and APOBEC3B (p = 0.015) protein expression were associated with increased VE-821 sensitivity. HGS cells had increased levels of RS (pRPASer4/8 and γH2AX nuclear immunofluorescence), and elevated RS predicted sensitivity to VE-821 independently of the cell line subtype. These data suggest that functional assessment of RS biomarkers may be a better predictive biomarker of ATRi response than any single aberrant gene in ovarian cancer and potentially other cancers.

Targeting the key players of DNA Repair Pathways as Cancer Therapeutics

The DNA Damage Response (DDR) is essentially a complicated network of cellular pathways involving a vast array of signalling proteins that help in maintaining the genome integrity of the cell and its turmoil is one of the hallmarks of cancer. Longestablished treatment of cancer with radiation therapies or genotoxic chemotherapies has exploited the defects in the DNA damage response for therapeutic application. The recent strategies for targeted therapy aim on inhibiting the DNA damage response in cancer which offers a greater potential by tailoring treatment to patients with tumours lacking specific DDR functions. This out-manoeuvres one of the key limitations of many DNA-damaging therapies, which is their inability in selectively targeting cancer cells that in turn leads to toxic effects on healthy cells and disastrous effects for patients. This review highlights the different concepts of DNA damage and repair mechanisms that exist in a living cell. In addition, it discusses the small molecule inhibitors of DDR pathway that seem to be promising cancer therapeutics.

Therapeutic Targeting of DNA Damage Response in Cancer.

DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.

Reactive oxygen species and DNA damage response in cancer.

Compared with normal cells, cancer cells often have an increase in reactive oxygen species (ROS) level. This high level of ROS allows the activation of different pathways essential for cellular transformation and tumorigenesis development. Increase of ROS can be due to increase of production or decrease of detoxification, both situations being well described in various cancers. Oxidative stress is involved at every step of cancer development from the initiation to the metastasis. How ROS arise is still a matter of debates and may vary with tissues, cell types or other conditions and may happen following a large diversity of mechanisms. Both oncogenic and tumor suppressor mutations can lead to an increase of ROS. In this chapter, I review how ROS are produced and detoxified and how ROS can damage DNA leading to the genomic instability featured in cancers.

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer.

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein posttranslational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double-strand break (DSB) repair and resistance to therapy-induced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response (DDR) in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DDR pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase or simply treating animals with GlcNAc protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DDR, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. IMPLICATIONS: The finding that the HBP, via its impact on protein O-GlcNAcylation, is a key determinant of the DDR in cancer provides a mechanistic link between metabolic reprogramming, genomic instability, and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization.

State-of-the-art strategies for targeting the DNA damage response in cancer.

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

Targeting Oxidatively Induced DNA Damage Response in Cancer: Opportunities for Novel Cancer Therapies

Cancer is a death cause in economically developed countries that results growing also in developing countries. Improved outcome through targeted interventions faces the scarce selectivity of the therapies and the development of resistance to them that compromise the therapeutic effects. Genomic instability is a typical cancer hallmark due to DNA damage by genetic mutations, reactive oxygen and nitrogen species, ionizing radiation, and chemotherapeutic agents. DNA lesions can induce and/or support various diseases, including cancer. The DNA damage response (DDR) is a crucial signaling-transduction network that promotes cell cycle arrest or cell death to repair DNA lesions. DDR dysregulation favors tumor growth as downregulated or defective DDR generates genomic instability, while upregulated DDR may confer treatment resistance. Redox homeostasis deeply and capillary affects DDR as ROS activate/inhibit proteins and enzymes integral to DDR both in healthy and cancer cells, although by different routes. DDR regulation through modulating ROS homeostasis is under investigation as anticancer opportunity, also in combination with other treatments since ROS affect DDR differently in the patients during cancer development and treatment. Here, we highlight ROS-sensitive proteins whose regulation in oxidatively induced DDR might allow for selective strategies against cancer that are better tailored to the patients.

Abstract IA10: Targeting the DNA damage response in cancer: Progress in the clinic

Abstract Genomic instability is a recognized hallmark of cancer and is associated with a predilection for cumulative DNA damage. In contrast to cytotoxic chemotherapy and radiotherapy, targeting critical aberrations involved in the DNA damage response (DDR) of cancer cells permits greater tumor selectivity against tumors with deficient DDR function, while sparing normal tissue. Poly(ADP-ribose) polymerase (PARP) inhibitors are the first class of antitumor agents to exploit cellular weaknesses in DNA repair through the concept of synthetic lethality. Since the pivotal studies in 2005 that demonstrated the exquisite sensitivity of BRCA1 and BRCA2 (BRCA1/2) mutant cell lines and xenografts to PARP inhibition, great progress has been made in developing single agent PARP inhibitors for use in the Clinic. Early phase clinical trials demonstrated that olaparib was well tolerated, with single agent activity in patients with BRCA1/2 mutation ovarian, breast, pancreatic and castration-resistant prostate cancers. In 2014, olaparib (Lynparza; AstraZeneca) was the first PARP inhibitor to be approved by the European Medicines Agency (EMA) as maintenance therapy for responding patients with BRCA1/2 mutant ovarian cancer following platinum-based chemotherapy, and the first to obtain accelerated approval by the US Food and Drug Administration (FDA) for advanced BRCA1/2 mutant ovarian cancer. There are also multiple other potent and bona fide PARP inhibitors, including rucaparib (AGO14699; Clovis), talazoparib (BMN673; Medivation), niraparib (MK4827; Tesaro) and veliparib (ABT-888; Abbvie), which are all currently in late phase clinical trial development. A number of critical questions remain in terms of optimizing and widening the clinical efficacy and utility of PARP inhibitors, respectively. While benefits are observed following PARP inhibitor treatment in patients with a range of tumor types with germline BRCA1/2 mutations, it is now clear that clinical efficacy is not restricted to this niche population of patients. Potential antitumor strategies may include successfully characterizing other predictive biomarkers of response or defining unique PARP inhibitor combination regimens. Such novel combinations include those with molecularly targeted agents against the PI3K-AKT and angiogenic pathways, as well as immune checkpoint inhibitors. Apart from PARP inhibitors, other novel antitumor agents against key DDR targets such as ATR and Wee1 kinase are showing promise in early phase clinical trials. The first-in-class ATR inhibitor VX-970 (Vertex Pharmaceuticals) was well tolerated as monotherapy and in combination with carboplatin chemotherapy, with preliminary evidence of target modulation and early signals of antitumor activity in DDR aberrant cancers. VX-970 is currently being explored in early phase I/II studies involving multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer; and in patients with DDR aberrations. AZD1775 (AstraZeneca) is a first-in-class Wee1 inhibitor, which was well tolerated with preliminary single-agent activity in patients harboring BRCA1/2 mutations. AZD1775 was also well tolerated in combination with carboplatin chemotherapy, with promising antitumor activity in p53 mutated ovarian cancer refractory or resistant to standard first line therapy. Citation Format: Timothy A. Yap. Targeting the DNA damage response in cancer: Progress in the clinic. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA10.

Linking Cancer Metabolism to DNA Repair and Accelerated Senescence.

Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability. By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.

Development of DNA Damage Response Signaling Biomarkers using Automated, Quantitative Image Analysis

The DNA damage response (DDR) coordinates DNA repair with cell cycle checkpoints to ameliorate or mitigate the pathological effects of DNA damage. Automated quantitative analysis (AQUA) and Tissue Studio are commercial technologies that use digitized immunofluorescence microscopy images to quantify antigen expression in defined tissue compartments. Because DDR is commonly activated in cancer and may reflect genetic instability within the lesion, a method to quantify DDR in cancer offers potential diagnostic and/or prognostic value. In this study, both AQUA and Tissue Studio algorithms were used to quantify the DDR in radiation-damaged skin fibroblasts, melanoma cell lines, moles, and primary and metastatic melanomas. Digital image analysis results for three markers of DDR (γH2AX, P-ATM, P-Chk2) correlated with immunoblot data for irradiated fibroblasts, whereas only γH2AX and P-Chk2 correlated with immunoblot data in melanoma cell lines. Melanoma cell lines displayed substantial variation in γH2AX and P-Chk2 expression, and P-Chk2 expression was significantly correlated with radioresistance. Moles, primary melanomas, and melanoma metastases in brain, lung and liver displayed substantial variation in γH2AX expression, similar to that observed in melanoma cell lines. Automated digital analysis of immunofluorescent images stained for DDR biomarkers may be useful for predicting tumor response to radiation and chemotherapy.

Posttranscriptional regulation of gene expression—adding another layer of complexity to the DNA damage response

In response to DNA damage, cells activate a complex, kinase-based signaling network to arrest the cell cycle and allow time for DNA repair, or, if the extend of damage is beyond repair capacity, induce apoptosis. This signaling network, which is collectively referred to as the DNA damage response (DDR), is primarily thought to consist of two components—a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes and a delayed transcriptional response that promotes a prolonged cell cycle arrest through the induction of Cdk inhibitors, such as p21. In recent years a third layer of complexity has emerged that involves potent posttranscriptional regulatory mechanisms that control the cellular response to DNA damage. Although much has been written on the relevance of the DDR in cancer and on the post-transcriptional role of microRNAs (miRs) in cancer, the post-transcriptional regulation of the DDR by non-coding RNAs and RNA-binding proteins (RBPs) still remains elusive in large parts. Here, we review the recent developments in this exciting new area of research in the cellular response to genotoxic stress. We put specific emphasis on the role of RBPs and the control of their function through DNA damage-activated protein kinases.

PIG3: A novel link between oxidative stress and DNA damage response in cancer

Reactive oxygen species (ROS), the most prominent free radicals produced in cells, can have both beneficial and detrimental effects on them. Many genes are known to be involved in ROS regulation. P53 inducible gene 3 (PIG3 or TP53I3) was identified in an analysis of genes induced by p53 before the onset of apoptosis. It is a widely conserved gene between many species. Until now it has been shown to exert two disparate cellular roles. The first is that of ROS producer linked to p53 induced apoptosis. In this context, it exhibits a NADPH dependent reductase activity with orthoquinones. The second is that of a component of the DNA damage response pathway. While it is considered as a p53 dependent pro-apoptotic gene, it is rarely affected in cancer. This data does not support an anti-tumor activity. In the present review we present and discuss aspects on the regulation and function of this factor and how it is implicated in cancer. We conclude by proposing that PIG3 may possibly have a role in cancer cell survival.

Abstract 2160: Critical BRCA1 role as a transcriptional regulator in prostate cancer DNA damage response

Abstract Loss or mutation of the BRCA1 gene is associated with nearly 5% of all breast cancers. Since many cases of sporadic cancers that also show decreased BRCA1 expression are often associated with higher grade tumors, significant interest has developed in defining mechanisms of BRCA1 regulation at the level of transcription. BRCA1 plays numerous roles in regulating genome integrity. It interacts with crucial proteins and is considered a gene-specific transcriptional co-regulator; however, BRCA1's role in the transcriptional response to DNA damage is poorly understood. In this study we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. Using BRCA1-depleted or BRCA1-overexpressing human prostate cancer cell lines, we found that BRCA1 mediates apoptosis, cell cycle arrest and decreased viability in response to doxorubicin treatment. Furthermore, xenograft studies using human prostate carcinoma PC3 cells demonstrate that BRCA1 depletion results in increased tumor growth. In addition, genome-wide screens using the combined application of chromatin immunoprecipitation and microarray technology (ChIP-chip) reveals that BRCA1 is highly enriched at the promoters of greater than 1300 genes. Gene Ontology (GO) analysis of this “BRCA1 ChIP signature” reveals a significant enrichment in genes that function in cell cycle regulation and the response to DNA damage including “M phase”’ and “Mitotic checkpoint” terms, suggesting a specific role for BRCA1 in controlling mitotic events following genotoxic stress. We have validated multiple members of this BRCA1 ChIP signature including: BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, GADD153 and ATM. Further focused analysis reveals that BRCA1 occupancy at the ATM promoter increases its transcription and H2AX phosphorylation. Notably, following doxorubicin exposure, BRCA1 is released from the ATM promoter and redistributed to other genes like GADD153 where it induces expression, apoptosis and cell cycle arrest. RNAi depletion of GADD153 blocks BRCA1-dependent apoptosis and cell cycle arrest in response to doxorubicin, suggesting that GADD153 is required for BRCA1 mediated drug sensitivity. These findings define a novel mechanism through which BRCA1 influences cell fate decisions in response to genotoxic insult through direct transcriptional control of genes, including GADD153 and ATM. Thus, tumors with absent or reduced expression of BRCA1 are likely to show a marked resistance to chemotherapy for prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2160. doi:10.1158/1538-7445.AM2011-2160

ChemInform Abstract: Targeting the DNA Damage Response in Cancer

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.