Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 3169-3180 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 77 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 2017 |
Bibliographical note
Funding Information:This work was supported by NIH grants R01 CA157429 to X. Liu, R01 CA192894 to X. Liu, R01 CA196835 to X. Liu, R01 CA196634 to X. Liu, R01 AR059130 to N. Ahmad, R01 CA176748 to N. Ahmad, and R15 GM114713 to S. Yan. The work was also partially supported by Purdue University Center for Cancer Research (P30 CA023168).
Publisher Copyright:
© 2017 American Association for Cancer Research.
ASJC Scopus subject areas
- Oncology
- Cancer Research
