MutSβ-MutLβ-FANCJ Axis Mediates the Restart of DNA Replication After Fork Stalling at Cotranscriptional G4/R-loops

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Feb 7

PMID 38324687

Authors

Esin Isik

Kaustubh Shukla

Michaela Pospisilova

Christiane Konig

Martin Andrs

Satyajeet Rao

Vinicio Rosano

Jana Dobrovolna

Lumir Krejci

Pavel Janscak

Affiliations

Soon will be listed here.

Abstract

Transcription-replication conflicts (TRCs) induce formation of cotranscriptional RNA:DNA hybrids (R-loops) stabilized by G-quadruplexes (G4s) on the displaced DNA strand, which can cause fork stalling. Although it is known that these stalled forks can resume DNA synthesis in a process initiated by MUS81 endonuclease, how TRC-associated G4/R-loops are removed to allow fork passage remains unclear. Here, we identify the mismatch repair protein MutSβ, an MLH1-PMS1 heterodimer termed MutLβ, and the G4-resolving helicase FANCJ as factors that are required for MUS81-initiated restart of DNA replication at TRC sites in human cells. This DNA repair process depends on the G4-binding activity of MutSβ, the helicase activity of FANCJ, and the binding of FANCJ to MLH1. Furthermore, we show that MutSβ, MutLβ, and MLH1-FANCJ interaction mediate FANCJ recruitment to G4s. These data suggest that MutSβ, MutLβ, and FANCJ act in conjunction to eliminate G4/R-loops at TRC sites, allowing replication restart.

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