The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks

Junqiu Zhang, Xin Zhao, Lu Liu, Hao Dong Li, Liya Gu, Diego H. Castrillon, Guo-Min Li

Research output: Contribution to journalArticlepeer-review

Abstract

Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase ɛ (Polɛ), carrying a proline-to-arginine substitution at amino acid 286 (Polɛ-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. Polɛ-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells.

Original languageEnglish (US)
Pages (from-to)e2201738119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number40
DOIs
StatePublished - Oct 4 2022

Keywords

  • chromosome instability
  • MutSα
  • nascent strand degradation
  • replication fork stability

ASJC Scopus subject areas

  • General

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