Rev1 contributes to proper mitochondrial function via the PARP-NAD +-SIRT1-PGC1α axis

Sci Rep. 2017 Oct 2;7(1):12480. doi: 10.1038/s41598-017-12662-3.

Abstract

Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress. Here, we show that Rev1-deficiency in mouse embryo fibroblasts or mouse liver tissue is associated with replicative stress and mitochondrial dysfunction. In addition, Rev1-deficiency is associated with high poly(ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • DNA-Directed DNA Polymerase
  • Embryo, Mammalian
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Gene Expression Regulation
  • Liver / enzymology
  • Male
  • Membrane Potential, Mitochondrial / physiology
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / enzymology
  • Mitochondria, Liver / genetics*
  • NAD / metabolism
  • Nucleotidyltransferases / deficiency
  • Nucleotidyltransferases / genetics*
  • Oxidative Phosphorylation
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Poly(ADP-ribose) Polymerases / genetics*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Primary Cell Culture
  • Signal Transduction
  • Sirtuin 1 / genetics*
  • Sirtuin 1 / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • NAD
  • Adenosine Triphosphate
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Poly(ADP-ribose) Polymerases
  • Nucleotidyltransferases
  • DNA-Directed DNA Polymerase
  • Rev1 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1