Protein phosphatase 1 acts as a RIF1 effector to suppress DSB resection prior to Shieldin action
| Autor: | Chikashi Obuse, Shin-Ya Isobe, Koji Nagao, Anne D. Donaldson, Hiroyuki Sasanuma, Shin-ichiro Hiraga |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MRN
QH301-705.5 Telomere-Binding Proteins Cell Cycle Proteins Context (language use) Poly(ADP-ribose) Polymerase Inhibitors Article General Biochemistry Genetics and Molecular Biology Resection Olaparib chemistry.chemical_compound Pathway choice RIF1 Protein Phosphatase 1 HR Humans DNA Breaks Double-Stranded Biology (General) Homologous Recombination Shieldin NHEJ Endodeoxyribonucleases Base Sequence BRCA1 Protein Chemistry Effector Protein phosphatase 1 PP1 Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) CtIP MRN complex Multiprotein Complexes biological phenomena cell phenomena and immunity Homologous recombination DNA HeLa Cells Protein Binding |
| Zdroj: | Cell Reports, Vol 36, Iss 2, Pp 109383-(2021) Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary DNA double-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 3′ 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. Graphical abstract Highlights • PP1 acts as a RIF1 effector distinct from shieldin in DNA damage repair • PP1 accumulates at damage sites dependent on RIF1 and 53BP1 • RIF1-PP1 suppresses assembly of CtIP damage foci to limit resection initiation by MRN • PP1 and shieldin cooperate to prevent precocious HR in the early damage response Isobe et al. show that PP1 acts as a RIF1 effector distinct from shieldin in DNA damage repair. RIF1-PP1 inhibits the initiation of resection by CtIP-MRN prior to shieldin action. PP1 and shieldin, as RIF1 effectors, cooperate to suppress premature homologous recombination in the early stage of the damage response. |
| Databáze: | OpenAIRE |
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