Faculty Opinions recommendation of Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.

2015 ◽  
Author(s):  
Cheng-Ming Chiang
Keyword(s):  
Dna Damage ◽  
Homologous Recombination

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.

scholarly journals Effect of the expression of BRCA2 on spontaneous homologous recombination and DNA damage-induced nuclear foci in Saccharomyces cerevisiae

Mutagenesis ◽  
2013 ◽  
Vol 28 (2) ◽  
pp. 187-195 ◽  
Author(s):  
L. Spugnesi ◽  
C. Balia ◽  
A. Collavoli ◽  
E. Falaschi ◽  
V. Quercioli ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Nuclear Foci

P IX.17 Homologous recombination in CHO cell lines defective in DNA damage processing

1997 ◽  
Vol 379 (1) ◽  
pp. S65
Author(s):  
M. Kruszewski ◽  
H. Kruszewska ◽  
H. Inaba ◽  
P. Jeggo ◽  
I. Szumiel
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Cell Lines ◽  
Cho Cell

The Rad17 homologue ofArabidopsisis involved in the regulation of DNA damage repair and homologous recombination

2004 ◽  
Vol 38 (6) ◽  
pp. 954-968 ◽  
Author(s):  
Fabian Heitzeberg ◽  
I-Peng Chen ◽  
Frank Hartung ◽  
Nadiya Orel ◽  
Karel J. Angelis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals Recombinogenic Effects of DNA-Damaging Agents Are Synergistically Increased by Transcription inSaccharomyces cerevisiae: New Insights Into Transcription-Associated Recombination

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 457-466 ◽  
Author(s):  
M García-Rubio ◽  
P Huertas ◽  
S González-Barrera ◽  
A Aguilera
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Sequence ◽  
Direct Repeat ◽  
Methyl Methanesulfonate ◽  
Immunoglobulin Genes ◽  
Developmentally Regulated ◽  
Dna Damaging Agents ◽  
Regulated Promoters ◽  
Synergistic Increase

AbstractHomologous recombination of a particular DNA sequence is strongly stimulated by transcription, a phenomenon observed from bacteria to mammals, which we refer to as transcription-associated recombination (TAR). TAR might be an accidental feature of DNA chemistry with important consequences for genetic stability. However, it is also essential for developmentally regulated processes such as class switching of immunoglobulin genes. Consequently, it is likely that TAR embraces more than one mechanism. In this study we tested the possibility that transcription induces recombination by making DNA more susceptible to recombinogenic DNA damage. Using different plasmid-chromosome and direct-repeat recombination constructs in which transcription is driven from either the PGAL1- or the Ptet-regulated promoters, we haveshown that either 4-nitroquinoline-N-oxide (4-NQO) or methyl methanesulfonate (MMS) produces a synergistic increase of recombination when combined with transcription. 4-NQO and MMS stimulated recombination of a transcriptionally active DNA sequence up to 12,800- and 130-fold above the spontaneous levels observed in the absence of transcription, whereas 4-NQO and MMS alone increased recombination 193- and 4.5-fold, respectively. Our results provide evidence that TAR is due, at least in part, to the ability of transcription to enhance the accessibility of DNA to exogenous chemicals and internal metabolites responsible for recombinogenic lesions. We discuss possible parallelisms between the mechanisms of induction of recombination and mutation by transcription.

Association of Homologous Recombination-DNA Damage Response Gene Mutations with Immune Biomarkers in Gastroesophageal Cancers

2021 ◽  
pp. molcanther.0879.2020
Author(s):  
Michael Cerniglia ◽  
Joanne Xiu ◽  
Axel Grothey ◽  
Michael J Pishvaian ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Response ◽  
Gene Mutations ◽  
Response Gene ◽  
Immune Biomarkers ◽  
Damage Response

Genomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16187-e16187
Author(s):  
Yang Shao ◽  
Qiuxiang Ou ◽  
Zhenhao Fang ◽  
Rui Liu ◽  
Hua Bao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Genomic Instability ◽  
Biliary Tract ◽  
Large Scale ◽  
Excision Repair ◽  
State Transitions ◽  
Pathway Enrichment Analysis ◽  
Distal Cholangiocarcinoma ◽  
Tract Cancer

e16187 Background: Bile tract cancers are genetically and clinically heterogenous with a poor prognosis. Identifying novel biomarkers for targeted therapy is required to improve the clinical outcome of bile tract cancer patients. Methods: Tumor tissue samples of 482 Chinese biliary tract cancer (BTC) patients were genetically profiled using targeted next generation sequencing. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. The R package ReactomePA was used in pathway enrichment analysis. Genomic instability was characterized by an in-house developed NGS-based Homologous Recombination Deficiency (HRD) panel and a HRD score was an unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores. Results: The BTC cohort consisted of 135 gallbladder cancer (GBC), 73 intrahepatic cholangiocarcinoma (iCCA), 18 distal cholangiocarcinoma (dCCA), 14 perihilar cholangiocarcinoma (pCCA), while the remaining 242 BTC patients of no specific subtype information. Most frequently mutated genes included TP53 (56%), KRAS (25%), ARID1A (17%), SMAD4 (11%), and CDKN2A (10%) . A preliminary pathway analysis revealed that mutations of DNA damage repair (DDR) pathway genes were enriched in the cohort ( p< 1e-10), accounting for over 70% of the patients, particularly in homologous recombination repair (HRR), Fanconi anemia (FA), mismatch repair (MMR), and base excision repair (BER) genes. More specifically, approximately 50% of the cohort carried at least one mutation of the HRR genes (43%) or MMR genes (14%). Patients with impaired MMR had increased microsatellite instability status (MSI) comparing to those with wildtype MMR (33% vs. 3.1%, p< 0.0001), and patients harboring HRR mutations demonstrated elevated genomic instability than those without such mutations (median HRD: 18 vs.14, p < 0.05), indicative of potential response to poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damage agents. Furthermore, high TMB was found to be highly correlated with DDR gene alterations ( p =0.004). In addition, we observed higher mutation frequencies of BRCA1/2 genes (including somatic and germline) in GBCs in contrast to other BTC subtypes. Conclusions: We herein reported the genomic features of 482 Chinese BTC samples and highlighted the role of DDR pathways including HRR and MMR. These findings could be useful to establish treatment and diagnostic strategies for BTC patients based on genetic information.

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