Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression

J Cell Biol. 2012 Sep 3;198(5):793-8. doi: 10.1083/jcb.201205193. Epub 2012 Aug 27.

Abstract

The Chk2-mediated deoxyribonucleic acid (DNA) damage checkpoint pathway is important for mitochondrial DNA (mtDNA) maintenance. We show in this paper that mtDNA itself affects cell cycle progression. Saccharomyces cerevisiae rho(0) cells, which lack mtDNA, were defective in G1- to S-phase progression. Deletion of subunit Va of cytochrome c oxidase, inhibition of F(1)F(0) adenosine triphosphatase, or replacement of all mtDNA-encoded genes with noncoding DNA did not affect G1- to S-phase progression. Thus, the cell cycle progression defect in rho(0) cells is caused by loss of DNA within mitochondria and not loss of respiratory activity or mtDNA-encoded genes. Rad53p, the yeast Chk2 homologue, was required for inhibition of G1- to S-phase progression in rho(0) cells. Pif1p, a DNA helicase and Rad53p target, underwent Rad53p-dependent phosphorylation in rho(0) cells. Thus, loss of mtDNA activated an established checkpoint kinase that inhibited G1- to S-phase progression. These findings support the existence of a Rad53p-regulated checkpoint that regulates G1- to S-phase progression in response to loss of mtDNA.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Checkpoint Kinase 2
  • DNA Damage / genetics
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA, Fungal / genetics
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • G1 Phase / genetics*
  • Genes, cdc*
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism*
  • S Phase / genetics*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA, Fungal
  • DNA, Mitochondrial
  • Saccharomyces cerevisiae Proteins
  • Electron Transport Complex IV
  • Checkpoint Kinase 2
  • Protein-Serine-Threonine Kinases
  • RAD53 protein, S cerevisiae
  • Adenosine Triphosphatases
  • DNA Helicases