DNA-PK is activated by SIRT2 deacetylation to promote DNA double-strand break repair by non-homologous end joining
Abstract
DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ. SIRT2 deacetylase activity governs cellular resistance to DSB-inducing agents and promotes NHEJ. SIRT2 furthermore interacts with and deacetylates DNA-PKcs in response to IR. SIRT2 deacetylase activity facilitates DNA-PKcs interaction with Ku and localization to DSBs and promotes DNA-PK activation and phosphorylation of downstream NHEJ substrates. Moreover, targeting SIRT2 with AGK2, a SIRT2-specific inhibitor, augments the efficacy of IR in cancer cells and tumors. Our findings define a regulatory step for DNA-PK activation by SIRT2-mediated deacetylation, elucidating a critical upstream signaling event initiating the repair of DSBs by NHEJ. Furthermore, our data suggest that SIRT2 inhibition may be a promising rationale-driven therapeutic strategy for increasing the effectiveness of radiation therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 03, 2023
- Source ID
- 10.1093/nar/gkad549
Entities
People
- Anthony J. Davis
- Bassel El-rayes
- Boying Song
- David M Smalley
- David S Yu
- Diana Danelia
- Duc M. Duong
- Elizabeth V Minten
- Eric A. Ortlund
- Fatmata Sesay
- Ganji P Nagaraju
- Hui Zhang
- Nho C Luong
- Nicholas T Seyfried
- Pamelasara E Head
- Priya Kapoor-vazirani
- Ramona Haji-seyed-javadi
- Sandip K Rath
- Shi-ya Wang
- Shuyi Li
- Waaqo Daddacha
- William S Dynan
- Xingming Deng
- Xu Liu
- Ya Wang
Organizations
- Augusta University
- Emory University
- Georgia Tech
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institutes of Health
- United States Department of Defense
- University of Alabama
- University of Texas Southwestern Medical Center
- Winship Cancer Institute