Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination

J Cell Biol. 2006 Dec 4;175(5):703-8. doi: 10.1083/jcb.200606145. Epub 2006 Nov 27.

Abstract

Differential modifications of proliferating cell nuclear antigen (PCNA) determine DNA repair pathways at stalled replication forks. In yeast, PCNA monoubiquitination by the ubiquitin ligase (E3) yRad18 promotes translesion synthesis (TLS), whereas the lysine-63-linked polyubiquitination of PCNA by yRad5 (E3) promotes the error-free mode of bypass. The yRad5-dependent pathway is important to prevent genomic instability during replication, although its exact molecular mechanism is poorly understood. This mechanism has remained totally elusive in mammals because of the lack of apparent RAD5 homologues. We report that a putative tumor suppressor gene, SHPRH, is a human orthologue of yeast RAD5. SHPRH associates with PCNA, RAD18, and the ubiquitin-conjugating enzyme UBC13 (E2) and promotes methyl methanesulfonate (MMS)-induced PCNA polyubiquitination. The reduction of SHPRH by stable short hairpin RNA increases sensitivity to MMS and enhances genomic instability. Therefore, the yRad5/SHPRH-dependent pathway is a conserved and fundamental DNA repair mechanism that protects the genome from genotoxic stress.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Conserved Sequence
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism
  • Genomic Instability*
  • Humans
  • Molecular Sequence Data
  • Polyubiquitin / metabolism*
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Protein Structure, Tertiary
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • DNA-Binding Proteins
  • Proliferating Cell Nuclear Antigen
  • RAD18 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Polyubiquitin
  • UBC13 protein, S cerevisiae
  • Ubiquitin-Conjugating Enzymes
  • SHPRH protein, human
  • Ubiquitin-Protein Ligases
  • DNA Helicases