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

J 2024

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

ISIK, Esin; Kaustubh SHUKLA; Michaela POSPÍŠILOVÁ; Christiane KÖNIG; Martin ANDRS et. al.

Basic information

Original name

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

Authors

ISIK, Esin; Kaustubh SHUKLA; Michaela POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution); Christiane KÖNIG; Martin ANDRS; Satyajeet RAO; Vinicio ROSANO; Jana DOBROVOLNA (203 Czech Republic); Lumír KREJČÍ (203 Czech Republic, belonging to the institution) and Pavel JANSCAK (203 Czech Republic)

Edition

Science advances, WASHINGTON, AMER ASSOC ADVANCEMENT SCIENCE, 2024, 2375-2548

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 11.700 in 2023

RIV identification code

RIV/00216224:14110/24:00135721

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1126/sciadv.adk2685

UT WoS

001190871400013

EID Scopus

2-s2.0-85184737786

Keywords in English

MutSβ-MutLβ-FANCJ; DNA replication

Abstract

V originále

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

Links

GX21-22593X, research and development project

Name: Identifikace a charakterizace proteinů zahrnutých v metabolismu G-kvadruplexů a R-smyček a jejich vztah k replikaci DNA

MUNI/A/1603/2023, interní kód MU

Name: Biomedicínské vědy IV

Investor: Masaryk University, Biomedical Sciences IV

206292/E/17/Z, interní kód MU

Name: Mechanics and execution of homologous recombination - biophysics to the organism

Investor: Wellcome Trust

Cite

ISIK, Esin; Kaustubh SHUKLA; Michaela POSPÍŠILOVÁ; Christiane KÖNIG; Martin ANDRS; Satyajeet RAO; Vinicio ROSANO; Jana DOBROVOLNA; Lumír KREJČÍ and Pavel JANSCAK. MutSβ-MutLβ-FANCJ axis mediates the restart of DNA replication after fork stalling at cotranscriptional G4/R-loops. Science advances. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2024, vol. 10, No 6, p. 1-16. ISSN 2375-2548. Available from: https://dx.doi.org/10.1126/sciadv.adk2685.

@article{2387597,
   author = {Isik, Esin and Shukla, Kaustubh and Pospíšilová, Michaela and König, Christiane and Andrs, Martin and Rao, Satyajeet and Rosano, Vinicio and Dobrovolna, Jana and Krejčí, Lumír and Janscak, Pavel},
   article_location = {WASHINGTON},
   article_number = {6},
   doi = {http://dx.doi.org/10.1126/sciadv.adk2685},
   keywords = {MutSβ-MutLβ-FANCJ; DNA replication},
   language = {eng},
   issn = {2375-2548},
   journal = {Science advances},
   title = {MutSβ-MutLβ-FANCJ axis mediates the restart of DNA replication after fork stalling at cotranscriptional G4/R-loops},
   url = {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},
   volume = {10},
   year = {2024}
}

TY  - JOUR
ID  - 2387597
AU  - Isik, Esin - Shukla, Kaustubh - Pospíšilová, Michaela - König, Christiane - Andrs, Martin - Rao, Satyajeet - Rosano, Vinicio - Dobrovolna, Jana - Krejčí, Lumír - Janscak, Pavel
PY  - 2024
TI  - MutSβ-MutLβ-FANCJ axis mediates the restart of DNA replication after fork stalling at cotranscriptional G4/R-loops
JF  - Science advances
VL  - 10
IS  - 6
SP  - 1-16
EP  - 1-16
PB  - AMER ASSOC ADVANCEMENT SCIENCE
SN  - 23752548
KW  - MutSβ-MutLβ-FANCJ
KW  - DNA replication
UR  - 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
N2  - 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
ER  -

ISIK, Esin; Kaustubh SHUKLA; Michaela POSPÍŠILOVÁ; Christiane KÖNIG; Martin ANDRS; Satyajeet RAO; Vinicio ROSANO; Jana DOBROVOLNA; Lumír KREJČÍ and Pavel JANSCAK. MutSβ-MutLβ-FANCJ axis mediates the restart of DNA replication after fork stalling at cotranscriptional G4/R-loops. \textit{Science advances}. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2024, vol.~10, No~6, p.~1-16. ISSN~2375-2548. Available from: https://dx.doi.org/10.1126/sciadv.adk2685.

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