title: Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection.
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.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Steger
authors.forename: Olga
authors.initials: O
authors.lastname: Murina
authors.forename: Daniela
authors.initials: D
authors.lastname: Hühn
authors.forename: Lorenza P
authors.initials: LP
authors.lastname: Ferretti
authors.forename: Reto
authors.initials: R
authors.lastname: Walser
authors.forename: Kay
authors.initials: K
authors.lastname: Hänggi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Lafranchi
authors.forename: Christine
authors.initials: C
authors.lastname: Neugebauer
authors.forename: Shreya
authors.initials: S
authors.lastname: Paliwal
authors.forename: Pavel
authors.initials: P
authors.lastname: Janscak
authors.forename: Bertran
authors.initials: B
authors.lastname: Gerrits
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.forename: Oliver
authors.initials: O
authors.lastname: Zerbe
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Sartori
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases; D042822:Genomic Instability; D057809:HEK293 Cells; D059765:Homologous Recombination; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D004247:DNA; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase