TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity
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TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. / Moudry, Pavel; Watanabe, Kenji; Wolanin, Kamila M.; Bartkova, Jirina; Wassing, Isabel E.; Watanabe, Sugiko; Strauss, Robert; Pedersen, Rune Troelsgaard; Østergaard, Vibe Hallundbæk; Lisby, Michael; Andújar-Sánchez, Miguel; Maya-Mendoza, Apolinar; Esashi, Fumiko; Lukas, Jiri; Bartek, Jiri.
In: The Journal of Cell Biology, Vol. 212, No. 3, 2016, p. 281-288.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity
AU - Moudry, Pavel
AU - Watanabe, Kenji
AU - Wolanin, Kamila M.
AU - Bartkova, Jirina
AU - Wassing, Isabel E.
AU - Watanabe, Sugiko
AU - Strauss, Robert
AU - Pedersen, Rune Troelsgaard
AU - Østergaard, Vibe Hallundbæk
AU - Lisby, Michael
AU - Andújar-Sánchez, Miguel
AU - Maya-Mendoza, Apolinar
AU - Esashi, Fumiko
AU - Lukas, Jiri
AU - Bartek, Jiri
N1 - © 2016 Moudry et al.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1083/jcb.201507042
DO - 10.1083/jcb.201507042
M3 - Journal article
C2 - 26811421
VL - 212
SP - 281
EP - 288
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 3
ER -
ID: 160870332