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Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection.
- Source :
-
Molecular cell [Mol Cell] 2013 May 09; Vol. 50 (3), pp. 333-43. Date of Electronic Publication: 2013 Apr 25. - Publication Year :
- 2013
-
Abstract
- The regulation of DNA double-strand break (DSB) repair by phosphorylation-dependent signaling pathways is crucial for the maintenance of genome stability; however, remarkably little is known about the molecular mechanisms by which phosphorylation controls DSB repair. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, interacts with key DSB repair factors and affects the relative contributions of homologous recombination (HR) and nonhomologous end-joining (NHEJ) to DSB repair. We find that PIN1-deficient cells display reduced NHEJ due to increased DNA end resection, whereas resection and HR are compromised in PIN1-overexpressing cells. Moreover, we identify CtIP as a substrate of PIN1 and show that DSBs become hyperresected in cells expressing a CtIP mutant refractory to PIN1 recognition. Mechanistically, we provide evidence that PIN1 impinges on CtIP stability by promoting its ubiquitylation and subsequent proteasomal degradation. Collectively, these data uncover PIN1-mediated isomerization as a regulatory mechanism coordinating DSB repair.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Carrier Proteins genetics
Carrier Proteins metabolism
Cell Line
Cyclin-Dependent Kinase 2 genetics
Cyclin-Dependent Kinase 2 metabolism
DNA Breaks, Double-Stranded
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Endodeoxyribonucleases
Genomic Instability
HEK293 Cells
Homologous Recombination
Humans
NIMA-Interacting Peptidylprolyl Isomerase
Nuclear Proteins genetics
Nuclear Proteins metabolism
Phosphorylation
Ubiquitination
DNA genetics
DNA End-Joining Repair
Peptidylprolyl Isomerase genetics
Peptidylprolyl Isomerase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 50
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 23623683
- Full Text :
- https://doi.org/10.1016/j.molcel.2013.03.023