scholarly journals Competing interaction partners modulate the activity of Sgs1 helicase during DNA end resection

2019 ◽  
Vol 38 (13) ◽  
Author(s):  
Kristina Kasaciunaite ◽  
Fergus Fettes ◽  
Maryna Levikova ◽  
Peter Daldrop ◽  
Roopesh Anand ◽  
...  
Keyword(s):  
Interaction Partners ◽  
Dna End Resection ◽  
Competing Interaction ◽  
End Resection

Repair pathway choice for double-strand breaks

2020 ◽  
Vol 64 (5) ◽  
pp. 765-777 ◽  
Author(s):  
Yixi Xu ◽  
Dongyi Xu
Keyword(s):  
Cell Cycle ◽  
Double Strand Breaks ◽  
Homologous Region ◽  
Gene Repair ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Environmental Radiation ◽  
Strand Breaks ◽  
Dna End Resection ◽  
End Resection

Abstract Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.

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 HELB Is a Feedback Inhibitor of DNA End Resection

2016 ◽  
Vol 61 (3) ◽  
pp. 405-418 ◽  
Author(s):  
Ján Tkáč ◽  
Guotai Xu ◽  
Hemanta Adhikary ◽  
Jordan T.F. Young ◽  
David Gallo ◽  
...  
Keyword(s):  
Feedback Inhibitor ◽  
Dna End Resection ◽  
End Resection

scholarly journals SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

Cell Reports ◽  
2017 ◽  
Vol 20 (8) ◽  
pp. 1921-1935 ◽  
Author(s):  
Waaqo Daddacha ◽  
Allyson E. Koyen ◽  
Amanda J. Bastien ◽  
PamelaSara E. Head ◽  
Vishal R. Dhere ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Dna End Resection ◽  
End Resection

scholarly journals Induction of homologous recombination between sequence repeats by the activation induced cytidine deaminase (AID) protein

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jean-Marie Buerstedde ◽  
Noel Lowndes ◽  
David G Schatz
Keyword(s):  
Homologous Recombination ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Holliday Junctions ◽  
Mutagenic Potential ◽  
Activation Induced Cytidine Deaminase ◽  
Invasion Analysis ◽  
Dna End Resection ◽  
Cytidine Deamination ◽  
End Resection

The activation induced cytidine deaminase (AID) protein is known to initiate somatic hypermutation, gene conversion or switch recombination by cytidine deamination within the immunoglobulin loci. Using chromosomally integrated fluorescence reporter transgenes, we demonstrate a new recombinogenic activity of AID leading to intra- and intergenic deletions via homologous recombination of sequence repeats. Repeat recombination occurs at high frequencies even when the homologous sequences are hundreds of bases away from the positions of AID-mediated cytidine deamination, suggesting DNA end resection before strand invasion. Analysis of recombinants between homeologous repeats yielded evidence for heteroduplex formation and preferential migration of the Holliday junctions to the boundaries of sequence homology. These findings broaden the target and off-target mutagenic potential of AID and establish a novel system to study induced homologous recombination in vertebrate cells.

scholarly journals Human SIRT6 Promotes DNA End Resection Through CtIP Deacetylation

Science ◽  
2010 ◽  
Vol 329 (5997) ◽  
pp. 1348-1353 ◽  
Author(s):  
Abderrahmane Kaidi ◽  
Brian T. Weinert ◽  
Chunaram Choudhary ◽  
Stephen P. Jackson
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
Protein A ◽  
Strand Break ◽  
Dsb Repair ◽  
Interacting Protein ◽  
Dna Double Strand Break ◽  
Dna End Resection ◽  
Lysine Deacetylases ◽  
End Resection

SIRT6 belongs to the sirtuin family of protein lysine deacetylases, which regulate aging and genome stability. We found that human SIRT6 has a role in promoting DNA end resection, a crucial step in DNA double-strand break (DSB) repair by homologous recombination. SIRT6 depletion impaired the accumulation of replication protein A and single-stranded DNA at DNA damage sites, reduced rates of homologous recombination, and sensitized cells to DSB-inducing agents. We identified the DSB resection protein CtIP [C-terminal binding protein (CtBP) interacting protein] as a SIRT6 interaction partner and showed that SIRT6-dependent CtIP deacetylation promotes resection. A nonacetylatable CtIP mutant alleviated the effect of SIRT6 depletion on resection, thus identifying CtIP as a key substrate by which SIRT6 facilitates DSB processing and homologous recombination. These findings further clarify how SIRT6 promotes genome stability.

scholarly journals CTCF cooperates with CtIP to drive homologous recombination repair of double-strand breaks

2019 ◽  
Vol 47 (17) ◽  
pp. 9160-9179 ◽  
Author(s):  
Soon Young Hwang ◽  
Mi Ae Kang ◽  
Chul Joon Baik ◽  
Yejin Lee ◽  
Ngo Thanh Hang ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Critical Role ◽  
Control Point ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
C Terminus ◽  
Dna End Resection ◽  
End Resection

Abstract The pleiotropic CCCTC-binding factor (CTCF) plays a role in homologous recombination (HR) repair of DNA double-strand breaks (DSBs). However, the precise mechanistic role of CTCF in HR remains largely unclear. Here, we show that CTCF engages in DNA end resection, which is the initial, crucial step in HR, through its interactions with MRE11 and CtIP. Depletion of CTCF profoundly impairs HR and attenuates CtIP recruitment at DSBs. CTCF physically interacts with MRE11 and CtIP and promotes CtIP recruitment to sites of DNA damage. Subsequently, CTCF facilitates DNA end resection to allow HR, in conjunction with MRE11–CtIP. Notably, the zinc finger domain of CTCF binds to both MRE11 and CtIP and enables proficient CtIP recruitment, DNA end resection and HR. The N-terminus of CTCF is able to bind to only MRE11 and its C-terminus is incapable of binding to MRE11 and CtIP, thereby resulting in compromised CtIP recruitment, DSB resection and HR. Overall, this suggests an important function of CTCF in DNA end resection through the recruitment of CtIP at DSBs. Collectively, our findings identify a critical role of CTCF at the first control point in selecting the HR repair pathway.

scholarly journals The internal region of CtIP negatively regulates DNA end resection

2020 ◽  
Vol 48 (10) ◽  
pp. 5485-5498 ◽  
Author(s):  
Sean Michael Howard ◽  
Ilaria Ceppi ◽  
Roopesh Anand ◽  
Roger Geiger ◽  
Petr Cejka
Keyword(s):  
Homologous Recombination ◽  
Regulatory Function ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Internal Region ◽  
Dna End Resection ◽  
End Resection

Abstract DNA double-strand breaks are repaired by end-joining or homologous recombination. A key-committing step of recombination is DNA end resection. In resection, phosphorylated CtIP first promotes the endonuclease of MRE11–RAD50–NBS1 (MRN). Subsequently, CtIP also stimulates the WRN/BLM–DNA2 pathway, coordinating thus both short and long-range resection. The structure of CtIP differs from its orthologues in yeast, as it contains a large internal unstructured region. Here, we conducted a domain analysis of CtIP to define the function of the internal region in DNA end resection. We found that residues 350–600 were entirely dispensable for resection in vitro. A mutant lacking these residues was unexpectedly more efficient than full-length CtIP in DNA end resection and homologous recombination in vivo, and consequently conferred resistance to lesions induced by the topoisomerase poison camptothecin, which require high MRN–CtIP-dependent resection activity for repair. This suggested that the internal CtIP region, further mapped to residues 550–600, may mediate a negative regulatory function to prevent over resection in vivo. The CtIP internal deletion mutant exhibited sensitivity to other DNA-damaging drugs, showing that upregulated resection may be instead toxic under different conditions. These experiments together identify a region within the central CtIP domain that negatively regulates DNA end resection.

scholarly journals Mechanistic insight into the assembly of the HerA–NurA helicase–nuclease DNA end resection complex

2017 ◽  
Vol 45 (20) ◽  
pp. 12025-12038 ◽  
Author(s):  
Zainab Ahdash ◽  
Andy M. Lau ◽  
Robert Thomas Byrne ◽  
Katja Lammens ◽  
Alexandra Stüetzer ◽  
...  
Keyword(s):  
Mechanistic Insight ◽  
Dna End Resection ◽  
End Resection ◽  
Insight Into
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