p53 and p21 regulate error-prone DNA repair to yield a lower mutation load

Mol Cell. 2006 May 5;22(3):407-13. doi: 10.1016/j.molcel.2006.03.022.

Abstract

Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p21 to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p21. Loss of this regulation by inactivation of p53 or p21 causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability.

Publication types

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

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p21 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA / biosynthesis
  • DNA Repair / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Knockout
  • Mutagenesis / genetics*
  • Mutation / genetics*
  • Proliferating Cell Nuclear Antigen / chemistry
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / metabolism
  • Ultraviolet Rays

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Proliferating Cell Nuclear Antigen
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • DNA