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.

Basic information

Original name

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

Authors

MOVSESJAN, Karina (417 Kyrgyzstan, belonging to the institution), V. SANNINO (380 Italy), Ondrej BELÁŇ (703 Slovakia, belonging to the institution), Jarmila MLČOUŠKOVÁ (203 Czech Republic, belonging to the institution), Mário ŠPÍREK (703 Slovakia, belonging to the institution), V. COSTANZO (380 Italy) and Lumír KREJČÍ (203 Czech Republic, guarantor, belonging to the institution)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 8.032

RIV identification code

RIV/00216224:14110/17:00095172

Organization unit

Faculty of Medicine

DOI

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

UT WoS

000412686100005

Keywords in English

Fanconi anemia

Abstract

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.

Links

GA13-26629S, research and development project

Name: SUMO a stability genomu

Investor: Czech Science Foundation

GA17-17720S, research and development project

Name: Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

Investor: Czech Science Foundation

MUNI/M/1894/2014, interní kód MU

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

Investor: Masaryk University, INTERDISCIPLINARY - Interdisciplinary research projects

Citovat

MOVSESJAN, Karina, V. SANNINO, Ondrej BELÁŇ, Jarmila MLČOUŠKOVÁ, Mário ŠPÍREK, V. COSTANZO and Lumír KREJČÍ. Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection. Cell Reports. CAMBRIDGE: Cell Press, 2017, vol. 21, No 2, p. 333-340. ISSN 2211-1247. Available from: 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 and Lumír KREJČÍ. Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection. \textit{Cell Reports}. CAMBRIDGE: Cell Press, 2017, vol.~21, No~2, p.~333-340. ISSN~2211-1247. Available from: https://dx.doi.org/10.1016/j.celrep.2017.09.062.

Detailed Information on Publication Record