Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments
and Impair Replication Fork Protection

J 2017

Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection

MOVSESJAN, Karina, V. SANNINO, Ondrej BELÁŇ, Jarmila MLČOUŠKOVÁ, Mário ŠPÍREK et. al.

Základní údaje

Originální název

Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection

Autoři

MOVSESJAN, Karina (417 Kyrgyzstán, domácí), V. SANNINO (380 Itálie), Ondrej BELÁŇ (703 Slovensko, domácí), Jarmila MLČOUŠKOVÁ (203 Česká republika, domácí), Mário ŠPÍREK (703 Slovensko, domácí), V. COSTANZO (380 Itálie) a Lumír KREJČÍ (203 Česká republika, garant, domácí)

Vydání

Cell Reports, CAMBRIDGE, Cell Press, 2017, 2211-1247

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10601 Cell biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 8.032

Kód RIV

RIV/00216224:14110/17:00095172

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1016/j.celrep.2017.09.062

UT WoS

000412686100005

Klíčová slova anglicky

Fanconi anemia

Štítky

CF CRYO, EL OK, podil

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 18. 3. 2018 15:44, Soňa Böhmová

Anotace

V originále

Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts. Reconstitution of DNA protection in vitro revealed that the defect arises directly due to altered RAD51 properties. Both mutations induce pronounced structural changes and RAD51 filament destabilization that is not rescued by prevention of ATP hydrolysis due to aberrant ATP binding. Our results further interconnect the FA pathway with DNA replication and provide mechanistic insight into the role of RAD51 in recombination-independent mechanisms of genome maintenance.

Návaznosti

GA13-26629S, projekt VaV

Název: SUMO a stability genomu

Investor: Grantová agentura ČR, SUMO a stability genomu

GA17-17720S, projekt VaV

Název: Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

Investor: Grantová agentura ČR, Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

MUNI/M/1894/2014, interní kód MU

Název: Development of new MUS81 nuclease inhibitors as chemical biology probe with clinical progression

Investor: Masarykova univerzita, Development of new MUS81 nuclease inhibitors as chemical biology probe with clinical progression, INTERDISCIPLINARY - Mezioborové výzkumné projekty

Citovat

MOVSESJAN, Karina, V. SANNINO, Ondrej BELÁŇ, Jarmila MLČOUŠKOVÁ, Mário ŠPÍREK, V. COSTANZO a Lumír KREJČÍ. Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection. Cell Reports. CAMBRIDGE: Cell Press, 2017, roč. 21, č. 2, s. 333-340. ISSN 2211-1247. Dostupné z: https://dx.doi.org/10.1016/j.celrep.2017.09.062.

@article{1395559,
   author = {Movsesjan, Karina and Sannino, V. and Beláň, Ondrej and Mlčoušková, Jarmila and Špírek, Mário and Costanzo, V. and Krejčí, Lumír},
   article_location = {CAMBRIDGE},
   article_number = {2},
   doi = {http://dx.doi.org/10.1016/j.celrep.2017.09.062},
   keywords = {Fanconi anemia},
   language = {eng},
   issn = {2211-1247},
   journal = {Cell Reports},
   title = {Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection},
   volume = {21},
   year = {2017}
}

TY  - JOUR
ID  - 1395559
AU  - Movsesjan, Karina - Sannino, V. - Beláň, Ondrej - Mlčoušková, Jarmila - Špírek, Mário - Costanzo, V. - Krejčí, Lumír
PY  - 2017
TI  - Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection
JF  - Cell Reports
VL  - 21
IS  - 2
SP  - 333-340
EP  - 333-340
PB  - Cell Press
SN  - 22111247
KW  - Fanconi anemia
N2  - Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts. Reconstitution of DNA protection in vitro revealed that the defect arises directly due to altered RAD51 properties. Both mutations induce pronounced structural changes and RAD51 filament destabilization that is not rescued by prevention of ATP hydrolysis due to aberrant ATP binding. Our results further interconnect the FA pathway with DNA replication and provide mechanistic insight into the role of RAD51 in recombination-independent mechanisms of genome maintenance.
ER  -

MOVSESJAN, Karina, V. SANNINO, Ondrej BELÁŇ, Jarmila MLČOUŠKOVÁ, Mário ŠPÍREK, V. COSTANZO a Lumír KREJČÍ. Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection. \textit{Cell Reports}. CAMBRIDGE: Cell Press, 2017, roč.~21, č.~2, s.~333-340. ISSN~2211-1247. Dostupné z: https://dx.doi.org/10.1016/j.celrep.2017.09.062.

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