scholarly journals The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination and contributes to DSB repair within heterochromatin

2019 ◽  
Vol 48 (4) ◽  
pp. 1872-1885 ◽  
Author(s):  
Gabriel Kollárovič ◽  
Caitríona E Topping ◽  
Edward P Shaw ◽  
Anna L Chambers
Keyword(s):  
Homologous Recombination ◽  
Cancer Biology ◽  
Genome Stability ◽  
Strand Break ◽  
Double Strand Break ◽  
Chromatin Remodelling ◽  
Double Strand Break Repair ◽  
Dsb Repair ◽  
Break Repair ◽  
End Resection

Abstract Efficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes facilitate different DNA repair pathways, during different stages of the cell cycle and in varied chromatin environments. The contribution of remodelling factors to double-strand break repair within heterochromatin during G2 is unclear. The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We discover that HELLS facilitates homologous recombination at two-ended breaks and contributes to repair within heterochromatic regions during G2. HELLS promotes initiation of HR by facilitating end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.

The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination within heterochromatin

2018 ◽  
Author(s):  
G. Kollarovic ◽  
C. E. Topping ◽  
E. P. Shaw ◽  
A. L. Chambers
Keyword(s):  
Homologous Recombination ◽  
Cancer Biology ◽  
Genome Stability ◽  
Strand Break ◽  
Chromatin Remodelling ◽  
Dsb Repair ◽  
Icf Syndrome ◽  
Damage Response ◽  
Break Repair ◽  
End Resection

ABSTRACTEfficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes can facilitate different DNA repair pathways, during different stages of the cell cycle and in a range of chromatin environments. The contribution of remodelling factors to break repair within heterochromatin during G2 is unclear.The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We find that HELLS facilitates homologous recombination at two-ended breaks within heterochromatic regions during G2. HELLS enables end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.

Human INO80 chromatin-remodelling complex contributes to DNA double-strand break repair via the expression of Rad54B and XRCC3 genes

2010 ◽  
Vol 431 (2) ◽  
pp. 179-187 ◽  
Author(s):  
Eun-Jung Park ◽  
Shin-Kyoung Hur ◽  
Jongbum Kwon
Keyword(s):  
Chinese Hamster ◽  
Strand Break ◽  
Double Strand Break ◽  
Chromatin Remodelling ◽  
Double Strand Break Repair ◽  
Dsb Repair ◽  
Direct Role ◽  
Dna Double Strand Break ◽  
Break Repair ◽  
Repair Defect

Recent studies have shown that the SWI/SNF family of ATP-dependent chromatin-remodelling complexes play important roles in DNA repair as well as in transcription. The INO80 complex, the most recently described member of this family, has been shown in yeast to play direct role in DNA DSB (double-strand break) repair without affecting the expression of the genes involved in this process. However, whether this function of the INO80 complex is conserved in higher eukaryotes has not been investigated. In the present study, we found that knockdown of hINO80 (human INO80) confers DNA-damage hypersensitivity and inefficient DSB repair. Microarray analysis and other experiments have identified the Rad54B and XRCC3 (X-ray repair complementing defective repair in Chinese-hamster cells 3) genes, implicated in DSB repair, to be repressed by hINO80 deficiency. Chromatin immunoprecipitation studies have shown that hINO80 binds to the promoters of the Rad54B and XRCC3 genes. Re-expression of the Rad54B and XRCC3 genes rescues the DSB repair defect in hINO80-deficient cells. These results suggest that hINO80 assists DSB repair by positively regulating the expression of the Rad54B and XRCC3 genes. Therefore, unlike yeast INO80, hINO80 can contribute to DSB repair indirectly via gene expression, suggesting that the mechanistic role of this chromatin remodeller in DSB repair is evolutionarily diversified.

scholarly journals Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joonas A. Jamsen ◽  
Akira Sassa ◽  
David D. Shock ◽  
William A. Beard ◽  
Samuel H. Wilson
Keyword(s):  
Active Site ◽  
Dna Polymerases ◽  
Time Lapse ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dsb Repair ◽  
X Ray Crystallography ◽  
Polymerase Fidelity ◽  
Break Repair

AbstractOxidized dGTP (8-oxo-7,8-dihydro-2´-deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase μ undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (At). Rotation of At into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair.

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.

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