MutSβ-MutLβ-FANCJ axis mediates the restart of DNA replication after fork stalling at cotranscriptional G4/R-loops

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Authors

ISIK Esin SHUKLA Kaustubh POSPÍŠILOVÁ Michaela KÖNIG Christiane ANDRS Martin RAO Satyajeet ROSANO Vinicio DOBROVOLNA Jana KREJČÍ Lumír JANSCAK Pavel

Year of publication 2024
Type Article in Periodical
Magazine / Source Science advances
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.science.org/doi/full/10.1126/sciadv.adk2685?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
Doi http://dx.doi.org/10.1126/sciadv.adk2685
Keywords MutSß-MutLß-FANCJ; DNA replication
Description 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 MutSß, an MLH1-PMS1 heterodimer termed MutLß, 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 MutSß, the helicase activity of FANCJ, and the binding of FANCJ to MLH1. Furthermore, we show that MutSß, MutLß, and MLH1-FANCJ interaction mediate FANCJ recruitment to G4s. These data suggest that MutSß, MutLß, and FANCJ act in conjunction to eliminate G4/R-loops at TRC sites, allowing replication restart
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