Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA
stretches and fork DNA

J 2024

Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA

AKITA, Masaki; Paul GIRVAN; Mário ŠPÍREK; Jiří NOVÁČEK; David RUEDA et al.

Základní údaje

Originální název

Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA

Autoři

AKITA, Masaki; Paul GIRVAN; Mário ŠPÍREK; Jiří NOVÁČEK; David RUEDA; Zbyněk PROKOP a Lumír KREJČÍ

Vydání

Nucleic Acids Research, Oxford, Oxford University Press, 2024, 0305-1048

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 13.100

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/24:00137161

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

HOMOLOGOUS RECOMBINATION; FANCONI-ANEMIA; NUCLEOPROTEIN FILAMENTS; CONFER SUSCEPTIBILITY; BRC REPEATS; REPAIR; MUTATIONS; IDENTIFICATION; REVERSAL; PARALOGS

Štítky

14110513, 14314010, 143160, 143180, CF CRYO, CF PROT, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 17. 6. 2025 11:09, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

Homologous recombination (HR) factors are crucial for DSB repair and processing stalled replication forks. RAD51 paralogs, including RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, have emerged as essential tumour suppressors, forming two subcomplexes, BCDX2 and CX3. Mutations in these genes are associated with cancer susceptibility and Fanconi anaemia, yet their biochemical activities remain unclear. This study reveals a linear arrangement of BCDX2 subunits compared to the RAD51 ring. BCDX2 shows a strong affinity towards single-stranded DNA (ssDNA) via unique binding mechanism compared to RAD51, and a contribution of DX2 subunits in binding branched DNA substrates. We demonstrate that BCDX2 facilitates RAD51 loading on ssDNA by suppressing the cooperative requirement of RAD51 binding to DNA and stabilizing the filament. Notably, BCDX2 also promotes RAD51 loading on short ssDNA and reversed replication fork substrates. Moreover, while mutants defective in ssDNA binding retain the ability to bind branched DNA substrates, they still facilitate RAD51 loading onto reversed replication forks. Our study provides mechanistic insights into how the BCDX2 complex stimulates the formation of BRCA2-independent RAD51 filaments on short stretches of ssDNA present at ssDNA gaps or stalled replication forks, highlighting its role in genome maintenance and DNA repair.

Návaznosti

GX21-22593X, projekt VaV

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

LX22NPO5102, projekt VaV

Název: Národní ústav pro výzkum rakoviny (Akronym: NÚVR)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní ústav pro výzkum rakoviny, 5.1 EXCELES

101158508, interní kód MU

Název: TRIAD: Enhancing Synergism on Telomere Function in Health and Disease

Investor: Evropská unie, TRIAD: Enhancing Synergism on Telomere Function in Health and Disease, Rozšiřování účasti a posílení ERA

857560, interní kód MU
(Kód CEP: EF17_043/0009632)

Název: CETOCOEN Excellence (Akronym: CETOCOEN Excellence)

Investor: Evropská unie, CETOCOEN Excellence, Spreading excellence and widening participation

90242, velká výzkumná infrastruktura

Název: CIISB III

90269, velká výzkumná infrastruktura

Název: RECETOX RI II

Přiložené soubory

gkae770.pdf

2434878.pdf

Citovat

AKITA, Masaki; Paul GIRVAN; Mário ŠPÍREK; Jiří NOVÁČEK; David RUEDA; Zbyněk PROKOP a Lumír KREJČÍ. Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA. Nucleic Acids Research. Oxford: Oxford University Press, 2024, roč. 52, č. 19, s. 11738-11752. ISSN 0305-1048. Dostupné z: https://doi.org/10.1093/nar/gkae770.

@article{2434878,
   author = {Akita, Masaki and Girvan, Paul and Špírek, Mário and Nováček, Jiří and Rueda, David and Prokop, Zbyněk and Krejčí, Lumír},
   article_location = {Oxford},
   article_number = {19},
   doi = {https://doi.org/10.1093/nar/gkae770},
   keywords = {HOMOLOGOUS RECOMBINATION; FANCONI-ANEMIA; NUCLEOPROTEIN FILAMENTS; CONFER SUSCEPTIBILITY; BRC REPEATS; REPAIR; MUTATIONS; IDENTIFICATION; REVERSAL; PARALOGS},
   language = {eng},
   issn = {0305-1048},
   journal = {Nucleic Acids Research},
   note = {Nedoplňovat EF17_043/0009632.},
   title = {Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA},
   url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkae770/7755874?login=true},
   volume = {52},
   year = {2024}
}

TY  - JOUR
ID  - 2434878
AU  - Akita, Masaki - Girvan, Paul - Špírek, Mário - Nováček, Jiří - Rueda, David - Prokop, Zbyněk - Krejčí, Lumír
PY  - 2024
TI  - Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA
JF  - Nucleic Acids Research
VL  - 52
IS  - 19
SP  - 11738-11752
EP  - 11738-11752
PB  - Oxford University Press
SN  - 03051048
N1  - Nedoplňovat EF17_043/0009632.
KW  - HOMOLOGOUS RECOMBINATION
KW  - FANCONI-ANEMIA
KW  - NUCLEOPROTEIN FILAMENTS
KW  - CONFER SUSCEPTIBILITY
KW  - BRC REPEATS
KW  - REPAIR
KW  - MUTATIONS
KW  - IDENTIFICATION
KW  - REVERSAL
KW  - PARALOGS
UR  - https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkae770/7755874?login=true
N2  - Homologous recombination (HR) factors are crucial for DSB repair and processing stalled replication forks. RAD51 paralogs, including RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, have emerged as essential tumour suppressors, forming two subcomplexes, BCDX2 and CX3. Mutations in these genes are associated with cancer susceptibility and Fanconi anaemia, yet their biochemical activities remain unclear. This study reveals a linear arrangement of BCDX2 subunits compared to the RAD51 ring. BCDX2 shows a strong affinity towards single-stranded DNA (ssDNA) via unique binding mechanism compared to RAD51, and a contribution of DX2 subunits in binding branched DNA substrates. We demonstrate that BCDX2 facilitates RAD51 loading on ssDNA by suppressing the cooperative requirement of RAD51 binding to DNA and stabilizing the filament. Notably, BCDX2 also promotes RAD51 loading on short ssDNA and reversed replication fork substrates. Moreover, while mutants defective in ssDNA binding retain the ability to bind branched DNA substrates, they still facilitate RAD51 loading onto reversed replication forks. Our study provides mechanistic insights into how the BCDX2 complex stimulates the formation of BRCA2-independent RAD51 filaments on short stretches of ssDNA present at ssDNA gaps or stalled replication forks, highlighting its role in genome maintenance and DNA repair.
ER  -

AKITA, Masaki; Paul GIRVAN; Mário ŠPÍREK; Jiří NOVÁČEK; David RUEDA; Zbyněk PROKOP a Lumír KREJČÍ. Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA. \textit{Nucleic Acids Research}. Oxford: Oxford University Press, 2024, roč.~52, č.~19, s.~11738-11752. ISSN~0305-1048. Dostupné z: https://doi.org/10.1093/nar/gkae770.

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