scholarly journals DEK is required for homologous recombination repair of DNA breaks

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Eric A. Smith ◽  
Boris Gole ◽  
Nicholas A. Willis ◽  
Rebeca Soria ◽  
Linda M. Starnes ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
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 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 ATR inhibition enhances 5-fluorouracil sensitivity independent of non-homologous end-joining and homologous recombination repair pathway

2020 ◽  
Author(s):  
Soichiro S. Ito ◽  
Yosuke Nakagawa ◽  
Masaya Matsubayashi ◽  
Yoshihiko M. Sakaguchi ◽  
Shinko Kobashigawa ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
End Joining ◽  
Drug Induced ◽  
Nucleotide Synthesis ◽  
Double Strand Dna Breaks ◽  
Recombination Repair ◽  
Non Homologous End Joining

ABSTRACTThe anticancer agent, 5-fluorouracil (5-FU), is typically applied in the treatment of various types of cancers because of its properties. Thought to be an inhibitor of the enzyme thymidylate synthase which plays a role in nucleotide synthesis, 5-FU has been found to induce single- and double-strand DNA breaks. The activation of ATR occurs as a reaction to UV- and chemotherapeutic drug-induced replication stress. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity. Using western blotting, we found that 5-FU treatment led to the phosphorylation of ATR. Surviving fractions were remarkably decreased in 5-FU with ATR inhibitor (ATRi) compared to 5-FU with other major DNA repair kinases inhibitors. 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 could induce the activation of intra-S checkpoint. Surprisingly, BRCA2-deficient cells were sensitive to 5-FU in the presence of ATRi. In addition, ATR inhibition enhanced the efficacy of 5-FU treatment, independent of non-homologous end-joining and homologous recombination repair pathways. Findings from the present study suggest ATR as a potential therapeutic target for 5-FU chemotherapy.

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 5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair

Oncotarget ◽  
2015 ◽  
Vol 6 (14) ◽  
pp. 12574-12586 ◽  
Author(s):  
Upadhyayula Sai Srinivas ◽  
Jerzy Dyczkowski ◽  
Tim Beißbarth ◽  
Jochen Gaedcke ◽  
Wael Y. Mansour ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Tumor Cells ◽  
Colorectal Tumor ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
Double Stranded Dna ◽  
Recombination Repair

scholarly journals NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks

2014 ◽  
Vol 42 (10) ◽  
pp. 6365-6379 ◽  
Author(s):  
Pierre-Alexandre Vidi ◽  
Jing Liu ◽  
Daniela Salles ◽  
Swaathi Jayaraman ◽  
George Dorfman ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
Recombination Repair

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.

scholarly journals DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Prasun Chakraborty ◽  
Kevin Hiom
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Rna Polymerase Ii ◽  
Critical Role ◽  
Dna Breaks ◽  
Double Stranded Dna ◽  
Recombination Repair ◽  
Dna End Resection ◽  
End Resection ◽  
Rna Polymerase Ii Transcription

AbstractDouble stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.

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