The ADP-ribose hydrolase NUDT5 is important for DNA repair

Cell Rep. 2022 Dec 20;41(12):111866. doi: 10.1016/j.celrep.2022.111866.

Abstract

DNA damage leads to rapid synthesis of poly(ADP-ribose) (pADPr), which is important for damage signaling and repair. pADPr chains are removed by poly(ADP-ribose) glycohydrolase (PARG), releasing free mono(ADP-ribose) (mADPr). Here, we show that the NUDIX hydrolase NUDT5, which can hydrolyze mADPr to ribose-5-phosphate and either AMP or ATP, is recruited to damage sites through interaction with PARG. NUDT5 does not regulate PARP or PARG activity. Instead, loss of NUDT5 reduces basal cellular ATP levels and exacerbates the decrease in cellular ATP that occurs during DNA repair. Further, loss of NUDT5 activity impairs RAD51 recruitment, attenuates the phosphorylation of key DNA-repair proteins, and reduces both H2A.Z exchange at damage sites and repair by homologous recombination. The ability of NUDT5 to hydrolyze mADPr, and/or regulate cellular ATP, may therefore be important for efficient DNA repair. Targeting NUDT5 to disrupt PAR/mADPr and energy metabolism may be an effective anti-cancer strategy.

Keywords: ATP; CP: Cell biology; CP: Molecular biology; DNA repair; NUDIX hydrolase; NUDT5; PARPs; chromatin; energy metabolism; homologous recombination; mono(ADP-ribose).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose* / metabolism
  • Adenosine Triphosphate
  • DNA Damage
  • DNA Repair*
  • Glycoside Hydrolases / metabolism
  • Poly Adenosine Diphosphate Ribose / metabolism

Substances

  • Adenosine Diphosphate Ribose
  • Poly Adenosine Diphosphate Ribose
  • Glycoside Hydrolases
  • Adenosine Triphosphate