scholarly journals Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance

2015 ◽  
Vol 763 ◽  
pp. 258-266 ◽  
Author(s):  
Brittany Haynes ◽  
Nadia Saadat ◽  
Brian Myung ◽  
Malathy P.V. Shekhar
Keyword(s):  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Translesion Synthesis ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Repair Pathways ◽  
Crosslink Repair

scholarly journals Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways

2020 ◽  
Vol 295 (37) ◽  
pp. 12946-12961
Author(s):  
Soichiro S. Ito ◽  
Yosuke Nakagawa ◽  
Masaya Matsubayashi ◽  
Yoshihiko M. Sakaguchi ◽  
Shinko Kobashigawa ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Mammalian Cells ◽  
Cell Cycle Checkpoint ◽  
Nonhomologous End Joining ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
End Joining ◽  
Nucleotide Synthesis ◽  
Recombination Repair ◽  
Repair Pathways

The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV– and chemotherapeutic drug–induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU–treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU–based chemotherapy.

scholarly journals DNAH2 facilitates the homologous recombination repair of Fanconi anemia pathway through modulating FANCD2 ubiquitination

Blood Science ◽  
2021 ◽  
Vol 3 (3) ◽  
pp. 71-77
Author(s):  
Lixian Chang ◽  
Xingjie Gao ◽  
Yuxia Wang ◽  
Chunmin Huang ◽  
Min Gao ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Homologous Recombination Repair ◽  
Fanconi Anemia Pathway ◽  
Recombination Repair

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.

scholarly journals Current gene panels account for nearly all homologous recombination repair-associated multiple-case breast cancer families

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Thibaut S. Matis ◽  
Nadia Zayed ◽  
Bouchra Labraki ◽  
Manon de Ladurantaye ◽  
Théophane A. Matis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Large Fraction ◽  
Homologous Recombination Repair ◽  
Mutational Signatures ◽  
Recombination Repair ◽  
Multiple Case ◽  
Gene Panels ◽  
Tumor Dna

AbstractIt was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

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