TY - JOUR
T1 - DNA-PK is activated by SIRT2 deacetylation to promote DNA double-strand break repair by non-homologous end joining
AU - Head, Pamela Sara E.
AU - Kapoor-Vazirani, Priya
AU - Nagaraju, Ganji P.
AU - Zhang, Hui
AU - Rath, Sandip K.
AU - Luong, Nho C.
AU - Haji-Seyed-Javadi, Ramona
AU - Sesay, Fatmata
AU - Wang, Shi Ya
AU - Duong, Duc M.
AU - Daddacha, Waaqo
AU - Minten, Elizabeth V.
AU - Song, Boying
AU - Danelia, Diana
AU - Liu, Xu
AU - Li, Shuyi
AU - Ortlund, Eric A.
AU - Seyfried, Nicholas T.
AU - Smalley, David M.
AU - Wang, Ya
AU - Deng, Xingming
AU - Dynan, William S.
AU - El-Rayes, Bassel
AU - Davis, Anthony J.
AU - Yu, David S.
N1 - Publisher Copyright:
© The Author(s ) 2023.
PY - 2023/8/25
Y1 - 2023/8/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85168799131&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168799131&partnerID=8YFLogxK
U2 - 10.1093/nar/gkad549
DO - 10.1093/nar/gkad549
M3 - Article
C2 - 37395399
AN - SCOPUS:85168799131
SN - 0305-1048
VL - 51
SP - 7972
EP - 7987
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 15
ER -