Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

P. Moudry, K. Watanabe, KM. Wolanin, J. Bartkova, IE. Wassing, S. Watanabe, R. Strauss, R. Troelsgaard Pedersen, VH. Oestergaard, M. Lisby, M. Andújar-Sánchez, A. Maya-Mendoza, F. Esashi, J. Lukas, J. Bartek,

. 2016 ; 212 (3) : 281-8. [pub] 20160125

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc16020005

Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOPBP1's role in HR, with potential clinical implications for cancer treatment.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc16020005
003      
CZ-PrNML
005      
20250506121832.0
007      
ta
008      
160722s2016 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1083/jcb.201507042 $2 doi
024    7_
$a 10.1083/jcb.201507042 $2 doi
035    __
$a (PubMed)26811421
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Moudry, Pavel $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic.
245    10
$a TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity / $c P. Moudry, K. Watanabe, KM. Wolanin, J. Bartkova, IE. Wassing, S. Watanabe, R. Strauss, R. Troelsgaard Pedersen, VH. Oestergaard, M. Lisby, M. Andújar-Sánchez, A. Maya-Mendoza, F. Esashi, J. Lukas, J. Bartek,
520    9_
$a Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOPBP1's role in HR, with potential clinical implications for cancer treatment.
650    _2
$a transportní proteiny $x genetika $x metabolismus $7 D002352
650    _2
$a proteiny buněčného cyklu $x metabolismus $7 D018797
650    _2
$a chromatin $x metabolismus $7 D002843
650    12
$a restrukturace chromatinu $7 D042002
650    _2
$a DNA vazebné proteiny $x genetika $x metabolismus $7 D004268
650    _2
$a vztah mezi dávkou a účinkem léčiva $7 D004305
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a HeLa buňky $7 D006367
650    12
$a homologní rekombinace $7 D059765
650    _2
$a lidé $7 D006801
650    _2
$a jaderné proteiny $x genetika $x metabolismus $7 D009687
650    _2
$a nádory vaječníků $x farmakoterapie $x enzymologie $x genetika $x patologie $7 D010051
650    _2
$a fosforylace $7 D010766
650    _2
$a ftalaziny $x farmakologie $7 D010793
650    _2
$a piperaziny $x farmakologie $7 D010879
650    _2
$a PARP inhibitory $x farmakologie $7 D000067856
650    _2
$a vazba proteinů $7 D011485
650    _2
$a interakční proteinové domény a motivy $7 D054730
650    _2
$a protein-serin-threoninkinasy $x metabolismus $7 D017346
650    _2
$a protoonkogenní proteiny $x metabolismus $7 D011518
650    _2
$a RNA interference $7 D034622
650    _2
$a rekombinasa Rad51 $x genetika $x metabolismus $7 D051135
650    _2
$a signální transdukce $x účinky léků $7 D015398
650    _2
$a časové faktory $7 D013997
650    _2
$a transfekce $7 D014162
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Watanabe, Kenji $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
700    1_
$a Wolanin, Kamila M $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
700    1_
$a Bartkova, Jirina $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark Department of Medical Biochemistry and Biophysics, Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute, 17121 Solna, Sweden.
700    1_
$a Wassing, Isabel E $u The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK.
700    1_
$a Watanabe, Sugiko $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
700    1_
$a Strauss, Robert $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
700    1_
$a Troelsgaard Pedersen, Rune $u Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
700    1_
$a Oestergaard, Vibe H $u Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
700    1_
$a Lisby, Michael $u Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
700    1_
$a Andújar-Sánchez, Miguel $u Department of Pathology, Familial and Hereditary Cancer Unit, University Hospital, 35010 Las Palmas de Gran Canaria, Spain. $7 gn_A_00006824
700    1_
$a Maya-Mendoza, Apolinar $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
700    1_
$a Esashi, Fumiko $u The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK.
700    1_
$a Lukas, Jiri $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
700    1_
$a Bártek, Jiří, $d 1953- $u Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic Department of Medical Biochemistry and Biophysics, Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute, 17121 Solna, Sweden jb@cancer.dk. $7 xx0046271
773    0_
$w MED00002575 $t The Journal of cell biology $x 1540-8140 $g Roč. 212, č. 3 (2016), s. 281-8
856    41
$u https://pubmed.ncbi.nlm.nih.gov/26811421 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20160722 $b ABA008
991    __
$a 20250506121831 $b ABA008
999    __
$a ok $b bmc $g 1154675 $s 944533
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2016 $b 212 $c 3 $d 281-8 $e 20160125 $i 1540-8140 $m The Journal of cell biology $n J Cell Biol $x MED00002575
LZP    __
$a Pubmed-20160722
Back

Find record

Citation metrics

Archiving options