Repriming of DNA Synthesis at Stalled Replication Forks by Human PrimPol

Nat Struct Mol Biol. 2013 Dec;20(12):1383-9. doi: 10.1038/nsmb.2719. Epub 2013 Nov 17.

Abstract

DNA replication forks that collapse during the process of genomic duplication lead to double-strand breaks and constitute a threat to genomic stability. The risk of fork collapse is higher in the presence of replication inhibitors or after UV irradiation, which introduces specific modifications in the structure of DNA. In these cases, fork progression may be facilitated by error-prone translesion synthesis (TLS) DNA polymerases. Alternatively, the replisome may skip the damaged DNA, leaving an unreplicated gap to be repaired after replication. This mechanism strictly requires a priming event downstream of the lesion. Here we show that PrimPol, a new human primase and TLS polymerase, uses its primase activity to mediate uninterrupted fork progression after UV irradiation and to reinitiate DNA synthesis after dNTP depletion. As an enzyme involved in tolerance to DNA damage, PrimPol might become a target for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Breaks, Double-Stranded
  • DNA Damage
  • DNA Primase / chemistry
  • DNA Primase / metabolism
  • DNA Primase / physiology*
  • DNA Replication / physiology*
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / metabolism
  • DNA-Directed DNA Polymerase / physiology*
  • Genomic Instability
  • Humans
  • Multifunctional Enzymes / chemistry
  • Multifunctional Enzymes / metabolism
  • Multifunctional Enzymes / physiology*
  • RNA, Messenger / metabolism
  • S Phase
  • Ultraviolet Rays

Substances

  • Multifunctional Enzymes
  • RNA, Messenger
  • DNA Primase
  • PrimPol protein, human
  • DNA-Directed DNA Polymerase