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SUMOylation mediates CtIP's functions in DNA end resection and replication fork protection.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2021 Jan 25; Vol. 49 (2), pp. 928-953. - Publication Year :
- 2021
-
Abstract
- Double-strand breaks and stalled replication forks are a significant threat to genomic stability that can lead to chromosomal rearrangements or cell death. The protein CtIP promotes DNA end resection, an early step in homologous recombination repair, and has been found to protect perturbed forks from excessive nucleolytic degradation. However, it remains unknown how CtIP's function in fork protection is regulated. Here, we show that CtIP recruitment to sites of DNA damage and replication stress is impaired upon global inhibition of SUMOylation. We demonstrate that CtIP is a target for modification by SUMO-2 and that this occurs constitutively during S phase. The modification is dependent on the activities of cyclin-dependent kinases and the PI-3-kinase-related kinase ATR on CtIP's carboxyl-terminal region, an interaction with the replication factor PCNA, and the E3 SUMO ligase PIAS4. We also identify residue K578 as a key residue that contributes to CtIP SUMOylation. Functionally, a CtIP mutant where K578 is substituted with a non-SUMOylatable arginine residue is defective in promoting DNA end resection, homologous recombination, and in protecting stalled replication forks from excessive nucleolytic degradation. Our results shed further light on the tightly coordinated regulation of CtIP by SUMOylation in the maintenance of genome stability.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Amino Acid Substitution
Arginine chemistry
Ataxia Telangiectasia Mutated Proteins metabolism
Cell Line
Cyclin-Dependent Kinases metabolism
DNA Breaks, Double-Stranded
DNA End-Joining Repair genetics
Endodeoxyribonucleases chemistry
Endodeoxyribonucleases metabolism
Genes, Reporter
Genomic Instability
Humans
Lysine chemistry
Poly-ADP-Ribose Binding Proteins physiology
Proliferating Cell Nuclear Antigen metabolism
Protein Inhibitors of Activated STAT physiology
Protein Interaction Mapping
RNA Interference
RNA, Small Interfering genetics
RNA, Small Interfering pharmacology
Recombinant Fusion Proteins metabolism
Recombinational DNA Repair genetics
Recombinational DNA Repair physiology
DNA End-Joining Repair physiology
DNA Replication
Endodeoxyribonucleases physiology
Protein Processing, Post-Translational
Sumoylation
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 49
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 33406258
- Full Text :
- https://doi.org/10.1093/nar/gkaa1232