• Something wrong with this record ?

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

K. Zadorozhny, V. Sannino, O. Beláň, J. Mlčoušková, M. Špírek, V. Costanzo, L. Krejčí,

. 2017 ; 21 (2) : 333-340.

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc18024579

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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc18024579
003      
CZ-PrNML
005      
20180711105746.0
007      
ta
008      
180709s2017 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.celrep.2017.09.062 $2 doi
035    __
$a (PubMed)29020621
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Zadorozhny, Karina $u Department of Biology, Masaryk University, 62500 Brno, Czech Republic.
245    10
$a Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection / $c K. Zadorozhny, V. Sannino, O. Beláň, J. Mlčoušková, M. Špírek, V. Costanzo, L. Krejčí,
520    9_
$a 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.
650    _2
$a adenosintrifosfát $x metabolismus $7 D000255
650    _2
$a zvířata $7 D000818
650    12
$a replikace DNA $7 D004261
650    _2
$a Fanconiho anemie $x genetika $7 D005199
650    _2
$a lidé $7 D006801
650    _2
$a homologní protein MRE11 $x metabolismus $7 D000076228
650    12
$a mutace $7 D009154
650    _2
$a vazba proteinů $7 D011485
650    _2
$a stabilita proteinů $7 D055550
650    _2
$a rekombinasa Rad51 $x genetika $x metabolismus $7 D051135
650    _2
$a Xenopus $7 D014981
655    _2
$a časopisecké články $7 D016428
700    1_
$a Sannino, Vincenzo $u DNA Metabolism Laboratory, IFOM-The Firc Institute of Molecular Oncology, 20139 Milan, Italy.
700    1_
$a Beláň, Ondrej $u Department of Biology, Masaryk University, 62500 Brno, Czech Republic.
700    1_
$a Mlčoušková, Jarmila $u Department of Biology, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, 656 91 Brno, Czech Republic.
700    1_
$a Špírek, Mário $u Department of Biology, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, 656 91 Brno, Czech Republic.
700    1_
$a Costanzo, Vincenzo $u DNA Metabolism Laboratory, IFOM-The Firc Institute of Molecular Oncology, 20139 Milan, Italy. Electronic address: vincenzo.costanzo@ifom.eu.
700    1_
$a Krejčí, Lumír $u Department of Biology, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, 656 91 Brno, Czech Republic; National Centre for Biomolecular Research, Masaryk University, 62500 Brno, Czech Republic. Electronic address: lkrejci@chemi.muni.cz.
773    0_
$w MED00188029 $t Cell reports $x 2211-1247 $g Roč. 21, č. 2 (2017), s. 333-340
856    41
$u https://pubmed.ncbi.nlm.nih.gov/29020621 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20180709 $b ABA008
991    __
$a 20180711110037 $b ABA008
999    __
$a ok $b bmc $g 1316710 $s 1021500
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2017 $b 21 $c 2 $d 333-340 $i 2211-1247 $m Cell reports $n Cell Rep $x MED00188029
LZP    __
$a Pubmed-20180709

Find record

Citation metrics

Archiving options