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 DHX9-dependent recruitment of BRCA1 to RNA is required to promote DNA end resection in homologous recombination

2019 ◽  
Author(s):  
Prasun Chakraborty ◽  
Kevin Hiom
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Pivotal Role ◽  
Dna Breaks ◽  
Early Step ◽  
Dna And Rna ◽  
Dna Damaging Agents ◽  
Mediator Protein ◽  
Dna End Resection ◽  
End Resection

AbstractDExD/H-box helicase 9 (DHX9/RNA helicaseA) is ubiquitously expressed ATP-dependent helicase that unwinds a variety of complex DNA and RNA secondary structures, suggesting it might have a role in DNA replication and the repair of DNA damage. Here we identify a pivotal role for DHX9 in homologous recombination (HR). Cells that are deficient in DHX9 are impaired in the generation of single stranded DNA (ssDNA) by DNA end resection. Consequently these cells fail to recruit RPA and RAD51 to sites of DNA damage and are hypersensitive to treatment with the DNA damaging agents camptothecin and Olaparib. A critical early step in the initiation of HR is the recruitment of BRCA1 mediator protein to DNA damage to promote DNA resection. We show here that recruitment of BRCA1 to DNA damage foci is dependent on its interaction with DHX9 to form the BRCA1-D complex, which binds to nascent RNA. Together our data identify a pivotal role for DHX9 in homologous recombination and highlight the important contribution of RNA in the recruitment of BRCA1 to DNA damage for the repair of DNA breaks

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 NuA4 and SAGA acetyltransferase complexes cooperate for repair of DNA breaks by homologous recombination

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009459
Author(s):  
Xue Cheng ◽  
Valérie Côté ◽  
Jacques Côté
Keyword(s):  
Homologous Recombination ◽  
Strand Break ◽  
Saga Complex ◽  
Loop Formation ◽  
Dna Breaks ◽  
Direct Role ◽  
Chromatin Remodelers ◽  
D Loop ◽  
Dna End Resection ◽  
End Resection

Chromatin modifying complexes play important yet not fully defined roles in DNA repair processes. The essential NuA4 histone acetyltransferase (HAT) complex is recruited to double-strand break (DSB) sites and spreads along with DNA end resection. As predicted, NuA4 acetylates surrounding nucleosomes upon DSB induction and defects in its activity correlate with altered DNA end resection and Rad51 recombinase recruitment. Importantly, we show that NuA4 is also recruited to the donor sequence during recombination along with increased H4 acetylation, indicating a direct role during strand invasion/D-loop formation after resection. We found that NuA4 cooperates locally with another HAT, the SAGA complex, during DSB repair as their combined action is essential for DNA end resection to occur. This cooperation of NuA4 and SAGA is required for recruitment of ATP-dependent chromatin remodelers, targeted acetylation of repair factors and homologous recombination. Our work reveals a multifaceted and conserved cooperation mechanism between acetyltransferase complexes to allow repair of DNA breaks by homologous recombination.

scholarly journals DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1

Nature ◽  
2004 ◽  
Vol 431 (7011) ◽  
pp. 1011-1017 ◽  
Author(s):  
Grzegorz Ira ◽  
Achille Pellicioli ◽  
Alitukiriza Balijja ◽  
Xuan Wang ◽  
Simona Fiorani ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Checkpoint ◽  
Checkpoint Activation ◽  
Dna End Resection ◽  
End Resection

scholarly journals And-1 is required for homologous recombination repair by regulating DNA end resection

2016 ◽  
Vol 45 (5) ◽  
pp. 2531-2545 ◽  
Author(s):  
Yongming Li ◽  
Zongzhu Li ◽  
Ruiqin Wu ◽  
Zhiyong Han ◽  
Wenge Zhu
Keyword(s):  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Dna End Resection ◽  
End Resection

scholarly journals ZGRF1 promotes end resection of DNA homologous recombination via forming complex with BRCA1/EXO1

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shuang Yan ◽  
Man Song ◽  
Jie Ping ◽  
Shu-ting Lai ◽  
Xiao-yu Cao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Mammalian Cells ◽  
Cell Cycle Checkpoint ◽  
Dependent Manner ◽  
Dna Breaks ◽  
M Cell ◽  
End Resection

AbstractTo maintain genomic stability, the mammalian cells has evolved a coordinated response to DNA damage, including activation of DNA repair and cell cycle checkpoint processes. Exonuclease 1 (EXO1)-dependent excision of DNA ends is important for the initiation of homologous recombination (HR) repair of DNA breaks, which is thought to play a key role in activating the ATR-CHK1 pathway to induce G2/M cell cycle arrest. But the mechanism is still not fully understood. Here, we report that ZGRF1 forms complexes with EXO1 as well as other repair proteins and promotes DNA repair through HR. ZGRF1 is recruited to DNA damage sites in a MDC1-RNF8-BRCA1 dependent manner. Furthermore, ZGRF1 is important for the recruitment of RPA2 to DNA damage sites and the following ATR-CHK1 mediated G2/M checkpoint in response to irradiation. ZGRF1 null cells show increased sensitivity to many DNA-damaging agents, especially PARPi and irradiation. Collectively,our findings identify ZGRF1 as a novel regulator of DNA end resection and G2/M checkpoint. ZGRF1 is a potential target of radiation and PARPi cancer therapy.

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 CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation

2012 ◽  
Vol 197 (7) ◽  
pp. 869-876 ◽  
Author(s):  
Arne Nedergaard Kousholt ◽  
Kasper Fugger ◽  
Saskia Hoffmann ◽  
Brian D. Larsen ◽  
Tobias Menzel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Dna Lesions ◽  
Cell Cycle Checkpoint ◽  
Dna Breaks ◽  
Checkpoint Signaling ◽  
Cycle Checkpoint ◽  
Dna End Resection ◽  
End Resection

To prevent accumulation of mutations, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homology-directed repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of ATR (ataxia telangiectasia mutated and Rad3 related) and CHK1 kinases to induce the cell cycle checkpoint. In this paper, we show that CHK1 was rapidly and robustly activated before detectable end resection. Moreover, we show that the key resection factor CtIP was dispensable for initial ATR–CHK1 activation after DNA damage by camptothecin and ionizing radiation. In contrast, we find that DNA end resection was critically required for sustained ATR–CHK1 checkpoint signaling and for maintaining both the intra–S- and G2-phase checkpoints. Consequently, resection-deficient cells entered mitosis with persistent DNA damage. In conclusion, we have uncovered a temporal program of checkpoint activation, where CtIP-dependent DNA end resection is required for sustained checkpoint signaling.

scholarly journals Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria Pilar Sanchez-Bailon ◽  
Soo-Youn Choi ◽  
Elizabeth R. Dufficy ◽  
Karan Sharma ◽  
Gavin S. McNee ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
Arginine Methylation ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Recombination Repair ◽  
Dna End Resection ◽  
End Resection

AbstractCross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway.

scholarly journals NuA4 and SAGA acetyltransferase complexes cooperate for repair of DNA breaks by homologous recombination

2021 ◽  
Author(s):  
Xue Cheng ◽  
Valerie Cote ◽  
Jacques Côté
Keyword(s):  
Homologous Recombination ◽  
Strand Break ◽  
Saga Complex ◽  
Loop Formation ◽  
Dna Breaks ◽  
Direct Role ◽  
Chromatin Remodelers ◽  
D Loop ◽  
Dna End Resection ◽  
End Resection

Chromatin modifying complexes play important yet not fully defined roles in DNA repair processes. The essential NuA4 histone acetyltransferase (HAT) complex is recruited to double-strand break (DSB) sites and spreads along with DNA end resection. As predicted, NuA4 acetylates surrounding nucleosomes upon DSB induction and defects in its activity correlate with altered DNA end resection and Rad51 recombinase recruitment. Importantly, we show that NuA4 is also recruited to the donor sequence during recombination along with increased H4 acetylation, indicating a direct role during strand invasion/D-loop formation after resection.  We found that NuA4 cooperates locally with another HAT, the SAGA complex, during DSB repair as their combined action is essential for DNA end resection to occur.  This cooperation of NuA4 and SAGA is required for recruitment of ATP-dependent chromatin remodelers, targeted acetylation of repair factors and homologous recombination. Our work reveals a multifaceted and conserved cooperation mechanism between acetyltransferase complexes to allow repair of DNA breaks by homologous recombination.

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