Protein phosphatase 1 acts as a RIF1 effector to suppress DSB resection prior to Shieldin action

Shin-Ya Isobe, Shin-ichiro Hiraga, Koji Nagao, Hiroyuki Sasanuma, Anne D. Donaldson, Chikashi Obuse*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

DNAdouble-strand breaks (DSBs) are repaired mainly by non-homologous end joining (NHEJ) or homologous recombination (HR). RIF1 negatively regulates resection through the effector Shieldin, which associates with a short 30 single-stranded DNA (ssDNA) overhang by the MRN (MRE11-RAD50-NBS1) complex, to prevent further resection and HR repair. In this study, we show that RIF1, but not Shieldin, inhibits the accumulation of CtIP at DSB sites immediately after damage, suggesting that RIF1 has another effector besides Shieldin. We find that protein phosphatase 1 (PP1), a known RIF1 effector in replication, localizes at damage sites dependent on RIF1, where it suppresses downstream CtIP accumulation and limits the resection by the MRN complex. PP1 therefore acts as a RIF1 effector distinct from Shieldin. Furthermore, PP1 deficiency in the context of Shieldin depletion elevates HR immediately after irradiation. We conclude that PP1 inhibits resection before the action of Shieldin to prevent precocious HR in the early phase of the damage response.

Original languageEnglish
Article number109383
Number of pages18
JournalCell Reports
Volume36
Issue number2
DOIs
Publication statusPublished - 13 Jul 2021

Keywords

  • RIF1
  • PP1
  • Resection
  • Shieldin
  • NHEJ
  • HR
  • Pathway Choice
  • CtiP
  • MRN
  • Olaparib

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