Phosphatase 1 nuclear targeting subunit mediates recruitment and function of poly (ADP-Ribose) polymerase 1 in DNA Repair

Feifei Wang, Songli Zhu, Laura A. Fisher, Ling Wang, Nicholas J. Eurek, James K Wahl, Li Lan, Aimin Peng

Research output: Contribution to journalArticle

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Abstract

PARP, particularly PARP1, plays an essential role in the detection and repair of DNA single-strand breaks and double- strand breaks. PARP1 accumulates at DNA damage sites within seconds after DNA damage to catalyze the massive induction of substrate protein poly ADP-ribosylation (PARylation). However, the molecular mechanisms underlying the recruitment and activation of PARP1 in DNA repair are not fully understood. Here we show that phosphatase 1 nuclear targeting subunit 1 (PNUTS) is a robust binding partner of PARP1. Inhibition of PNUTS led to strong accumulation of endogenous DNA damage and sensitized the cellular response to a wide range of DNA-damaging agents, implicating PNUTS as an essential and multifaceted regulator of DNA repair. Recruitment of PNUTS to laser-induced DNA damagewas similar to that of PARP1, and depletion or inhibition of PARP1 abrogated recruitment of PNUTS to sites of DNA damage. Conversely, PNUTS was required for efficient induction of substrate PARylation after DNA damage. PNUTS bound the BRCA1 C-terminal (BRCT) domain of PARP1 and was required for the recruitment of PARP1 to sites of DNA damage. Finally, depletion of PNUTS rendered cancer cells hypersensitive to PARP inhibition. Taken together, our study characterizes PNUTS as an essential partner of PARP1 in DNA repair and a potential drug target in cancer therapy. Significance: These findings reveal PNUTS as an essential functional partner of PARP1 in DNA repair and suggest its inhibition as a potential therapeutic strategy in conjunction with DNA-damaging agents or PARP inhibitors.

Original languageEnglish (US)
Pages (from-to)2526-2535
Number of pages10
JournalCancer Research
Volume79
Issue number10
DOIs
StatePublished - Jan 1 2019

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Phosphoric Monoester Hydrolases
DNA Repair
DNA Damage
Adenosine Diphosphate
DNA
Poly (ADP-Ribose) Polymerase-1
Single-Stranded DNA Breaks
Neoplasms
Lasers
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phosphatase 1 nuclear targeting subunit mediates recruitment and function of poly (ADP-Ribose) polymerase 1 in DNA Repair. / Wang, Feifei; Zhu, Songli; Fisher, Laura A.; Wang, Ling; Eurek, Nicholas J.; Wahl, James K; Lan, Li; Peng, Aimin.

In: Cancer Research, Vol. 79, No. 10, 01.01.2019, p. 2526-2535.

Research output: Contribution to journalArticle

Wang, Feifei ; Zhu, Songli ; Fisher, Laura A. ; Wang, Ling ; Eurek, Nicholas J. ; Wahl, James K ; Lan, Li ; Peng, Aimin. / Phosphatase 1 nuclear targeting subunit mediates recruitment and function of poly (ADP-Ribose) polymerase 1 in DNA Repair. In: Cancer Research. 2019 ; Vol. 79, No. 10. pp. 2526-2535.
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