ATM controls the extent of DNA end resection by eliciting sequential posttranslational modifications of CtIP.
Jinhua Han,Li Wan,Guixing Jiang,Liping Cao,Feiyu Xia,Tian Tian,Xiaomei Zhu,Mingjie Wu,Michael S.Y. Huen,Yi Wang,Ting Liu,Jun Huang +11 more
TLDR
In this paper, the authors show that upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner.Abstract:
DNA end resection is a critical step in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain unclear. Here, we show that, upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner. CtIP SUMOylation occurs on damaged chromatin and requires prior hyperphosphorylation by the ATM protein kinase. SUMO-modified hyperphosphorylated CtIP is targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. Consequently, disruption of CtIP SUMOylation results in aberrant accumulation of CtIP at DSBs, which, in turn, causes uncontrolled excessive resection, defective HR, and increased cellular sensitivity to DSB-inducing agents. These findings reveal a previously unidentified regulatory mechanism that regulates CtIP activity at DSBs and thus the extent of end resection via ATM-dependent sequential posttranslational modification of CtIP.read more
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ATM's Role in the Repair of DNA Double-Strand Breaks.
Atsushi Shibata,Penny A. Jeggo +1 more
TL;DR: In this article, the authors summarize the roles of ATM that focus on DNA double strand break repair in ataxia telangiectasia (A-T) cells and show that the redundancy of these stress responses impairs the accuracy of repair, consequently leading to dramatic sensitivity to ionizing radiation (IR) in AT-T cells.
Journal ArticleDOI
SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability.
TL;DR: Small ubiquitin-like modifier (SUMO)-targeted E3 UCLs (STUbLs) as discussed by the authors are specialized enzymes that recognize SUMOylated proteins and attach UCL to them, and participate in diverse molecular processes that span cell cycle regulated events.
Journal ArticleDOI
TOPORS-mediated RAD51 SUMOylation facilitates homologous recombination repair
Gurusamy Hariharasudhan,Seo Yeon Jeong,Min Ji Kim,Sung Mi Jung,Gwanwoo Seo,Ju-Ran Moon,Sumi Lee,In-Youb Chang,Younghoon Kee,Ho Jin You,Jung-Hee Lee +10 more
TL;DR: It is found that topoisomerase 1-binding arginine/serine-rich protein (TOPORS) induces the SUMOylation of RAD51 at lysine residues 57 and 70 in response to DNA damaging agents, demonstrating a crucial role for TOPORS-mediated RAD51 SUMOYLation in promoting HR repair and genomic maintenance.
Journal ArticleDOI
OUP accepted manuscript
TL;DR: In this paper , the SUMOylation of RAD51 is shown to be crucial for the RAD51 recruitment to chromatin and HR repair, and it is shown that SUMOYLation-deficient RAD51 reduces the association with its crucial binding partner BRCA2, explaining its deficiency in supporting the HR repair.
Journal ArticleDOI
BMI-1 regulates DNA end resection and homologous recombination repair.
Amira Fitieh,Andrew J. Locke,Fatemeh Mashayekhi,Fajr Khaliqdina,Amit Sharma,Ismail Hassan Ismail +5 more
TL;DR: In this article , the authors established a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection.
References
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Human CtIP promotes DNA end resection
Alessandro A. Sartori,Claudia Lukas,Julia Coates,Martin Mistrik,Shuang Fu,Jiri Bartek,Richard Baer,Jiri Lukas,Stephen P. Jackson +8 more
TL;DR: These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.
Journal ArticleDOI
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TL;DR: Research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels is reviewed.
Journal ArticleDOI
Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair
Pablo Huertas,Stephen P. Jackson +1 more
TL;DR: It is established that Thr-847 mutations to either Ala or Glu affect DSB repair efficiency, cause hypersensitivity toward DSB-generating agents, and affect the frequency and nature of radiation-induced chromosomal rearrangements, suggesting that CDK-mediated control of resection in human cells operates by mechanisms similar to those recently established in yeast.