Abstract / Description of output
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.
Original language | English |
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Pages (from-to) | 333-43 |
Number of pages | 11 |
Journal | Molecular Cell |
Volume | 50 |
Issue number | 3 |
DOIs | |
Publication status | Published - 9 May 2013 |
Keywords / Materials (for Non-textual outputs)
- Cyclin-Dependent Kinase 2
- DNA Breaks, Double-Stranded
- DNA-Binding Proteins
- Genomic Instability
- Homologous Recombination
- Peptidylprolyl Isomerase
- Phosphorylation
- Ubiquitination