Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining

Songli Zhu, Laura A. Fisher, Tadayoshi Bessho, Aimin Peng

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a key role in mediating nonhomologous end joining (NHEJ), a major repair pathway for DNA double-strand breaks (DSBs). The activation, function and dynamics of DNA-PKcs is regulated largely by its reversible phosphorylation at numerous residues, many of which are targeted by DNA-PKcs itself. Interestingly, these DNA-PKcs phosphorylation sites function in a distinct, and sometimes opposing manner, suggesting that they are differentially regulated via complex actions of both kinases and phosphatases. In this study we identified several phosphatase subunits as potential DSB-associated proteins. In particular, protein phosphatase 1 (PP1) is recruited to a DSB-mimicking substrate in Xenopusegg extracts and sites of laser microirradiation in human cells. Depletion of PP1 impairs NHEJ in both Xenopus egg extracts and human cells. PP1 binds multiple motifs of DNA-PKcs, regulates DNA-PKcs phosphorylation, and is required for DNA-PKcs activation after DNA damage. Interestingly, phosphatase 1 nuclear targeting subunit (PNUTS), an inhibitory regulator of PP1, is also recruited to DNA damage sites to promote NHEJ. PNUTS associates with the DNA-PK complex and is required for DNA-PKcs phosphorylation at Ser-2056 and Thr-2609. Thus, PNUTS and PP1 together finetune the dynamic phosphorylation of DNA-PKcs after DNA damage to mediate NHEJ.

Original languageEnglish (US)
Pages (from-to)10583-10594
Number of pages12
JournalNucleic acids research
Volume45
Issue number18
DOIs
StatePublished - Oct 1 2017

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DNA-Activated Protein Kinase
Protein Phosphatase 1
Phosphoric Monoester Hydrolases
Catalytic Domain
Phosphorylation
DNA Damage
Double-Stranded DNA Breaks
Xenopus
Cell Extracts
Ovum
Lasers
Phosphotransferases

ASJC Scopus subject areas

  • Genetics

Cite this

Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining. / Zhu, Songli; Fisher, Laura A.; Bessho, Tadayoshi; Peng, Aimin.

In: Nucleic acids research, Vol. 45, No. 18, 01.10.2017, p. 10583-10594.

Research output: Contribution to journalArticle

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