A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

Download Full-text

PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

International Journal of Molecular Sciences ◽

10.3390/ijms22105112 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5112

Author(s):

Lotte van Beek ◽

Éilís McClay ◽

Saleha Patel ◽

Marianne Schimpl ◽

Laura Spagnolo ◽

...

Keyword(s):

Dna Damage ◽

Dna Binding ◽

Parp Inhibitors ◽

Covalent Modification ◽

Activation Mechanism ◽

Cancer Therapies ◽

Damage Repair ◽

Complementary Role ◽

Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

Download Full-text

The emerging role of RNAs in DNA damage repair

Cell Death and Differentiation ◽

10.1038/cdd.2017.16 ◽

2017 ◽

Vol 24 (4) ◽

pp. 580-587 ◽

Cited By ~ 18

Author(s):

Ben R Hawley ◽

Wei-Ting Lu ◽

Ania Wilczynska ◽

Martin Bushell

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Critical Role ◽

Repair Process ◽

Rna Molecules ◽

Processing Enzymes ◽

Damage Repair ◽

New Findings ◽

Integral Role ◽

Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

Download Full-text

BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

Journal of Oncology ◽

10.1155/2020/4986365 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Carlo Messina ◽

Carlo Cattrini ◽

Davide Soldato ◽

Giacomo Vallome ◽

Orazio Caffo ◽

...

Keyword(s):

Prostate Cancer ◽

Parp Inhibitors ◽

Castration Resistant Prostate Cancer ◽

Brca Mutations ◽

Primary Tumors ◽

Receptor Signalling ◽

Castration Resistant ◽

Damage Repair ◽

Poor Outcomes

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.

Download Full-text

Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.389 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 389-389

Author(s):

Erkut Hasan Borazanci ◽

Carol Guarnieri ◽

Susan Haag ◽

Ronald Lee Korn ◽

Courtney Edwards Snyder ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Dna Repair ◽

Retrospective Analysis ◽

Pearson Correlation ◽

Brca2 Mutation ◽

Dna Damage Repair ◽

Parp Inhibitors ◽

Damage Repair ◽

Repair Deficiency

389 Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.

Download Full-text

Mystery of DNA repair: the role of the MRN complex and ATM kinase in DNA damage repair

Journal of Applied Genetics ◽

10.1007/bf03195638 ◽

2008 ◽

Vol 49 (4) ◽

pp. 383-396 ◽

Cited By ~ 48

Author(s):

Kamila Czornak ◽

Sanaullah Chughtai ◽

Krystyna H. Chrzanowska

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Repair ◽

Atm Kinase ◽

Mrn Complex ◽

Damage Repair

Download Full-text

DNA repair system defects - role in oncogenesis and cancer therapy

Kazan medical journal ◽

10.17816/kmj1503 ◽

2014 ◽

Vol 95 (3) ◽

pp. 307-314

Author(s):

S V Boychuk ◽

B R Ramazanov

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Therapy ◽

Single Case ◽

Published Data ◽

Repair System ◽

Damage Repair ◽

Anti Cancer ◽

Repair Mechanisms ◽

Acquired Abnormalities

Inherited and acquired abnormalities in DNA damage repair system may lead to cancer and other diseases, as well as to act as one of the key factors determining the patient’s responsiveness to chemo- and radiotherapy. Nowadays, the principles of the personalized therapy, based on specific features of disease development and pathogenesis of a solitary organism or in a small group, are applied to treat a broad number of diseases, including cancers. This approach allows to choose the most effective cancer therapy in every single case of cancer, based on the genetic analysis and expression level of specific proteins. One of the promising approaches for increasing the effectiveness of non-surgical cancer treatments - to develop the methods to increase the cancer cells sensitivity to conducted chemotherapy, based on using the DNA repair system defects for the better anti-cancer effect. The review covers some types of DNA repair system defects occurring while chemo- and radiotherapy. Perspectives of the possible influences on DNA repair mechanisms treated as possible targets for both anti-cancer treatment and for increasing the effects of cancer chemo- and radiotherapy, are discussed in the review considering the available published data and results of own research. DNA repair system defects play an important role in cancer genesis, but as well can determine the good response of patients with such defects to chemo- and radiotherapy (inducing different types of DNA damage).

Download Full-text

Post-translational modifications of lysine in DNA-damage repair

Essays in Biochemistry ◽

10.1042/bse0520093 ◽

2012 ◽

Vol 52 ◽

pp. 93-111 ◽

Cited By ~ 13

Author(s):

Snehajyoti Chatterjee ◽

Parijat Senapati ◽

Tapas K. Kundu

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Post Translational Modifications ◽

Dna Repair Mechanisms ◽

The Past ◽

Damage Repair ◽

Lysine Residues ◽

Repair Mechanisms ◽

Genotoxic Insult

DNA damage in cells is often the result of constant genotoxic insult. Nevertheless, efficient DNA repair pathways are able to maintain genomic integrity. Over the past decade it has been revealed that it is not only kinase signalling pathways which play a central role in this process, but also the different post-translational modifications at lysine residues of histone (chromatin) and non-histone proteins. These lysine modifications include acetylation, methylation, ubiquitination and SUMOylation. Genomic instability is often the major cause of different diseases, especially cancer, where lysine modifications are altered and thereby have an impact on the various DNA repair mechanisms. This chapter will discuss the recent advances in our understanding of the role of different lysine modifications in DNA repair and its physiological consequences.

Download Full-text

The role of oxidative DNA damage, DNA repair, GSTM1, SOD2 and OGG1 polymorphisms in individual susceptibility to Barrett’s esophagus

Toxicology and Industrial Health ◽

10.1177/0748233709359278 ◽

2010 ◽

Vol 26 (2) ◽

pp. 67-79 ◽

Cited By ~ 9

Author(s):

Ela Kadioglu ◽

Semra Sardas ◽

Meltem Ergun ◽

Selahattin Unal ◽

Ali Esat Karakaya

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Oxidative Dna Damage ◽

Repair Capacity ◽

Base Damage ◽

Purine Base ◽

Dna Repair Capacity ◽

Individual Susceptibility ◽

Damage Repair

Determination of the genetic alterations, which play a role in the etiology of Barrett’s esophagus (BE), could help identify high-risk individuals for esophageal adenocarcinoma (EA). The aim of the present study was to investigate the role of oxidative DNA damage, glutathione (GSH) concentration as oxidative stress parameters and DNA repair capacity, GSTM1, SOD1 Ala16Val and OGG1 Ser326Cys genetic polymorphisms as individual susceptibility parameters in the etiology of BE. The study groups comprised BE patients who were clinically diagnosed (n = 40) and a healthy control group (n = 40). Basal DNA damage, pyrimidine and purine base damage after H2O2 induction, H 2O2 sensitivity, DNA repair capacity, oxidized pyrimidine and purine base damage repair were evaluated in peripheral blood lymphocytes with a modified comet assay using specific endonucleases (Endo III and Fpg). Polymerase chain reaction—restriction length polymorphism (PCR-RFLP)-based assays were used for genotyping. The patient group showed elevated levels of basal DNA damage, pyrimidine base damage and H2O2 sensitivity as compared to controls (p < .05). DNA repair capacity, oxidized pyrimidine and purine base damage repair capacity, were not statistically different between patients and controls. GSH concentration was found to be significantly lower in smoking patients than in the controls (p < .05). None of the genetic variations changed the risk of having BE disease. However, patients carrying the variant OGG1 Cys allele showed elevated levels of pyrimidine base damage as compared to patients carrying the wild-type OGG1 Ser (p < .05). The results of this study point to a role of oxidative DNA damage in BE. However, DNA repair capacity, GSTM1, SOD1 Ala16Val and OGG1 Ser326Cys genetic polymorphisms appeared to play no role in the individual susceptibility to this disease.

Download Full-text

Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.801200 ◽

2022 ◽

Vol 9 ◽

Author(s):

Iain A. Richard ◽

Joshua T. Burgess ◽

Kenneth J. O’Byrne ◽

Emma Bolderson

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Catalytic Domain ◽

Current Knowledge ◽

Dna Damage Repair ◽

Cancer Therapeutics ◽

Parp Inhibitors ◽

Clinical Use ◽

Cellular Functions ◽

Damage Repair

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

Download Full-text

Deep Sequencing Discovery and Profiling of Known and Novel miRNAs Produced in Response to DNA Damage in Rice

International Journal of Molecular Sciences ◽

10.3390/ijms22189958 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9958

Author(s):

Jianxiang Zhang ◽

Cheng Xu ◽

Kangwei Liu ◽

Yaoqinq Li ◽

Mengna Wang ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Gene Transcription ◽

Target Genes ◽

Expression Patterns ◽

Dna Damage Repair ◽

Repair Process ◽

Differentially Expressed ◽

Damage Repair ◽

Differentially Expressed Mirnas

Under extreme environmental conditions such as ultraviolet and ionizing radiation, plants may suffer DNA damage. If these damages are not repaired accurately and rapidly, they may lead to chromosomal abnormalities or even cell death. Therefore, organisms have evolved various DNA repair mechanisms to cope with DNA damage which include gene transcription and post-translational regulation. MicroRNA (miRNA) is a type of non-coding single-stranded RNA molecule encoded by endogenous genes. They can promote DNA damage repair by regulating target gene transcription. Here, roots from seedlings of the japonica rice cultivar ‘Yandao 8’ that were treated with bleomycin were collected for transcriptome-level sequencing, using non-treated roots as controls. A total of 14,716,232 and 17,369,981 reads mapping to miRNAs were identified in bleomycin-treated and control groups, respectively, including 513 known and 72 novel miRNAs. Compared with the control group, 150 miRNAs showed differential expression levels. Target predictions of these differentially expressed miRNAs yielded 8731 potential gene targets. KEGG annotation and a gene ontology analysis indicated that the highest-ranked target genes were classified into metabolic processes, RNA degradation, DNA repair, and so on. Notably, the DNA repair process was significantly enriched in both analyses. Among these differentially expressed miRNAs, 58 miRNAs and 41 corresponding potential target genes were predicted to be related to DNA repair. RT-qPCR results confirmed that the expression patterns of 20 selected miRNAs were similar to those from the sequencing results, whereas four miRNAs gave opposite results. The opposing expression patterns of several miRNAs with regards to their target genes relating to the DNA repair process were also validated by RT-qPCR. These findings provide valuable information for further functional studies of miRNA involvement in DNA damage repair in rice.

Download Full-text