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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F16%3A33160762" target="_blank" >RIV/61989592:15110/16:33160762 - isvavai.cz</a>

Result on the web

<a href="http://jcb.rupress.org/content/212/3/281" target="_blank" >http://jcb.rupress.org/content/212/3/281</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1083/jcb.201507042" target="_blank" >10.1083/jcb.201507042</a>

Result language

angličtina

Original language name

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

Original language description

Topoisomerase II beta-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.

Czech name

—

Czech description

—

Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

—

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Cell Biology

ISSN

0021-9525

e-ISSN

—

Volume of the periodical

212

Issue of the periodical within the volume

3

Country of publishing house

US - UNITED STATES

Number of pages

8

Pages from-to

281-288

UT code for WoS article

000370487900005

EID of the result in the Scopus database

—