Orc6 is a component of the replication fork and enables efficient mismatch repair

Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2121406119. doi: 10.1073/pnas.2121406119. Epub 2022 May 27.

Abstract

In eukaryotes, the origin recognition complex (ORC) is required for the initiation of DNA replication. The smallest subunit of ORC, Orc6, is essential for prereplication complex (pre-RC) assembly and cell viability in yeast and for cytokinesis in metazoans. However, unlike other ORC components, the role of human Orc6 in replication remains to be resolved. Here, we identify an unexpected role for hOrc6, which is to promote S-phase progression after pre-RC assembly and DNA damage response. Orc6 localizes at the replication fork and is an accessory factor of the mismatch repair (MMR) complex. In response to oxidative damage during S phase, often repaired by MMR, Orc6 facilitates MMR complex assembly and activity, without which the checkpoint signaling is abrogated. Mechanistically, Orc6 directly binds to MutSα and enhances the chromatin-association of MutLα, thus enabling efficient MMR. Based on this, we conclude that hOrc6 plays a fundamental role in genome surveillance during S phase.

Keywords: ATR; DNA damage; Orc6; mismatch repair; replication.

Publication types

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

MeSH terms

  • DNA Mismatch Repair*
  • DNA-Binding Proteins / metabolism
  • Humans
  • MutL Proteins / metabolism
  • Origin Recognition Complex* / genetics
  • Origin Recognition Complex* / metabolism
  • Protein Binding
  • S Phase*

Substances

  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MutLalpha protein, human
  • ORC6 protein, human
  • Origin Recognition Complex
  • MutL Proteins