TY - JOUR
T1 - Plk1 phosphorylation of Mre11 antagonizes the DNA damage response
AU - Li, Zhiguo
AU - Li, Jie
AU - Kong, Yifan
AU - Yan, Shan
AU - Ahmad, Nihal
AU - Liu, Xiaoqi
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment.
AB - The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment.
UR - http://www.scopus.com/inward/record.url?scp=85021056820&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021056820&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-2787
DO - 10.1158/0008-5472.CAN-16-2787
M3 - Article
C2 - 28512243
AN - SCOPUS:85021056820
SN - 0008-5472
VL - 77
SP - 3169
EP - 3180
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -