Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma

2021 ◽  
pp. clincanres.1367.2021
Author(s):  
James M. Cleary ◽  
Brian M. Wolpin ◽  
Stephanie K Dougan ◽  
Srivatsan Raghavan ◽  
Harshabad Singh ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Pancreatic Adenocarcinoma ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Dna Repair Inhibitors

scholarly journals Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

2021 ◽  
Vol 11 (4) ◽  
pp. 245
Author(s):  
Laura Cortesi ◽  
Claudia Piombino ◽  
Angela Toss
Keyword(s):  
Prognostic Factors ◽  
Homologous Recombination ◽  
Pancreatic Adenocarcinoma ◽  
Objective Response ◽  
Metastatic Breast ◽  
Germline Mutations ◽  
Response To Treatment ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
Recombination Repair

The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

141 INDICATIONS FOR DNA DOUBLE-STRAND BREAK REPAIR IN EARLY BOVINE EMBRYOS

2007 ◽  
Vol 19 (1) ◽  
pp. 188
Author(s):  
A. Brero ◽  
D. Koehler ◽  
T. Cremer ◽  
E. Wolf ◽  
V. Zakhartchenko
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Strand Break ◽  
Dna Lesions ◽  
Homologous Recombination Repair ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Male And Female ◽  
Γh2ax Foci ◽  
Recombination Repair

DNA double-strand breaks (DSBs) are considered the most severe type of DNA lesions, because such lesions, if unrepaired, lead to a loss of genome integrity. Soon after induction of DSBs, chromatin surrounding the damage is modified by phosphorylation of the histone variant H2AX, generating so-called γH2AX, which is a hallmark of DSBs (Takahashi et al. 2005 Cancer Lett. 229, 171–179). γH2AX appears to be a signal for the recruitment of proteins constituting the DNA repair machinery. Depending on the type of damage and the cell cycle stage of the affected cell, DSBs are repaired either by nonhomologous end joining or by homologous recombination using the sister chromatid DNA as template (Hoeijmakers 2001 Nature 411, 366–374). We used immunofluorescence to analyze chromatin composition during bovine development and found γH2AX foci in both male and female pronuclei of IVF embryos. The number and size of foci varied considerably between embryos and between the male and female pronuclei. To test whether the observed γH2AX foci represented sites of active DNA repair, we co-stained IVF zygotes for γH2AX and 3 different proteins involved in homologous recombination repair of DSBs: NBS1 (phosphorylated at amino acid serine 343), 53BP1, and Rad51. We found co-localization of γH2AX foci with phosphorylated NBS1 as well as with Rad51 but did not observe the presence of 53BP1 at γH2AX foci in IVF zygotes. Our finding shows the presence of DSBs in IVF zygotes and suggests the capability of homologous recombination repair. The lack of 53BP1, a component of homologous recombination repair, which usually co-localizes with γH2AX foci at exogenously induced DSBs (Schultz et al. 2000 J. Cell. Biol. 151, 1381–1390) poses the possibility that the mechanism present in early embryos differs substantially from that involved in DNA repair of DSBs in somatic cells.

scholarly journals Homologous Recombination Repair Polymorphisms and the Risk for Osteosarcoma / Polimorfizam Gena Odgovornih Za Reparaciju Dnk Homolognom Rekombinacijom I Rizikza Pojavu Osteosarkoma

2015 ◽  
Vol 34 (2) ◽  
pp. 200-206 ◽  
Author(s):  
Katja Goričar ◽  
Viljem Kovač ◽  
Janez Jazbec ◽  
Janez Lamovec ◽  
Vita Dolžan
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Cancer Susceptibility ◽  
Homologous Recombination Repair ◽  
Nucleotide Polymorphisms ◽  
Dna Repair Mechanisms ◽  
Recombination Repair ◽  
Repair Mechanisms ◽  
Repair Genes

Summary Background: DNA repair mechanisms are essential for maintaining genome stability, and genetic variability in DNA repair genes may contribute to cancer susceptibility. Our aim was to evaluate the influence of polymorphisms in the homologous recombination repair genes XRCC3, RAD51, and NBN on the risk for osteosarcoma. Methods: In total, 79 osteosarcoma cases and 373 controls were genotyped for eight single nucleotide polymorphisms (SNPs) in XRCC3, RAD51, and NBN. Logistic regression was used to determine the association of these SNPs with risk for osteosarcoma. Results: None of the investigated SNPs was associated with risk for osteosarcoma in the whole cohort of patients, however, in patients diagnosed before the age of thirty years XRCC3 rs861539 C>T and NBN rs1805794 G>C were associated with significantly decreased risk for osteosarcoma (P=0.047, OR=0.54, 95% CI=0.30-0.99 and P=0.036, OR=0.42, 95% CI=0.19-0.94, respectively). Moreover, in the carriers of a combination of polymorphic alleles in both SNPs risk for osteosarcoma was decreased even more significantly (Ptrend=0.007). The risk for developing osteosarcoma was the lowest in patients with no wild-type alleles for both SNPs (P=0.039, OR=0.31, 95% CI=0.10-0.94). Conclusions: Our results suggest that polymorphisms in homologous recombination repair genes might contribute to risk for osteosarcoma in patients diagnosed below the age of thirty years.

scholarly journals METTL3 promotes homologous recombination repair and modulates chemotherapeutic response by regulating the EGF/Rad51 axis

2021 ◽  
Author(s):  
Enjie Li ◽  
Mingyue Xia ◽  
Yu Du ◽  
Kaili Long ◽  
Feng Ji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Drug Response ◽  
Homologous Recombination Repair ◽  
Chemotherapeutic Drug ◽  
Chemotherapeutic Response ◽  
Recombination Repair ◽  
Pivotal Mechanism

METTL3 and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in breast cancer (BC) cells. Knockdown of METTL3 sensitized BC cells to Adriamycin (ADR) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A "reader," YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.

scholarly journals Evaluating the Genotoxic and Cytotoxic Effects of Thymidine Analogs, 5-Ethynyl-2′-Deoxyuridine and 5-Bromo-2′-Deoxyurdine to Mammalian Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6631
Author(s):  
Jeremy S. Haskins ◽  
Cathy Su ◽  
Junko Maeda ◽  
Kade D. Walsh ◽  
Alexis H. Haskins ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Mammalian Cells ◽  
Chinese Hamster ◽  
Growth Delay ◽  
Homologous Recombination Repair ◽  
Wild Type ◽  
Cellular Division ◽  
Recombination Repair ◽  
Underlying Mechanisms

BrdU (bromodeoxyuridine) and EdU (ethynyldeoxyuridine) have been largely utilized as the means of monitoring DNA replication and cellular division. Although BrdU induces gene and chromosomal mutations and induces sensitization to photons, EdU‘s effects have not been extensively studied yet. Therefore, we investigated EdU’s potential cytotoxic and mutagenic effects and its related underlying mechanisms when administered to Chinese hamster ovary (CHO) wild type and DNA repair-deficient cells. EdU treatment displayed a higher cytotoxicity and genotoxicity than BrdU treatment. Cells with defective homologous recombination repair displayed a greater growth delay and severe inhibition of clonogenicity with EdU compared to wild type and other DNA repair-deficient cells. Inductions of sister chromatid exchange and hypoxanthine phosphorybosyl transferase (HPRT) mutation were observed in EdU-incorporated cells as well. Interestingly, on the other hand, EdU did not induce sensitization to photons to the same degree as BrdU. Our results demonstrate that elevated concentrations (similar to manufacturers suggested concentration; >5–10 μM) of EdU treatment were toxic to the cell cultures, particularly in cells with a defect in homologous recombination repair. Therefore, EdU should be administered with additional precautions.

scholarly journals E2F1 Promotes Progression of Bladder Cancer by Modulating RAD54L Involved in Homologous Recombination Repair

2020 ◽  
Vol 21 (23) ◽  
pp. 9025
Author(s):  
Jeong-Yeon Mun ◽  
Seung-Woo Baek ◽  
Won Young Park ◽  
Won-Tae Kim ◽  
Seon-Kyu Kim ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Homologous Recombination Repair ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Recombination Repair

DNA repair defects are important factors in cancer development. High DNA repair activity can affect cancer progression and chemoresistance. DNA double-strand breaks in cancer cells caused by anticancer agents can be restored by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Our previous study has identified E2F1 as a key gene in bladder cancer progression. In this study, DNA repair genes related to E2F1 were analyzed, and RAD54L involved in HRR was identified. In gene expression analysis of bladder cancer patients, the survival of patients with high RAD54L expression was shorter with cancer progression than in patients with low RAD54L expression. This study also revealed that E2F1 directly binds to the promoter region of RAD54L and regulates the transcription of RAD54L related to the HRR pathway. This study also confirmed that DNA breaks are repaired by RAD54L induced by E2F1 in bladder cancer cells treated with MMC. In summary, RAD54L was identified as a new target directly regulated by E2F1. Our results suggest that, E2F1 and RAD54L could be used as diagnostic markers for bladder cancer progression and represent potential therapeutic targets.

scholarly journals Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors

2019 ◽  
pp. 1-23 ◽  
Author(s):  
Jon H. Chung ◽  
Ninad Dewal ◽  
Ethan Sokol ◽  
Paul Mathew ◽  
Robert Whitehead ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Genomic Profiling ◽  
Prostate Tumors ◽  
Primary Tumors ◽  
Metastatic Site ◽  
Recombination Repair ◽  
Comprehensive Genomic Profiling

PURPOSE Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability. METHODS Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB]). RESULTS Frequently altered genes were TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%) GAs. BRCA1/2, ATR, and FANCA GAs were associated with high gLOH, whereas CDK12-altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon ( CCND1/ FGF19/ FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1 compared with primary tumors. CONCLUSION Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study.

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