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SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair
Author(s) -
Han Yang,
Huang Xin,
Cao Xiaoyu,
Li Yuchen,
Gao Lei,
Jia Jin,
Li Gang,
Guo Hejiang,
Liu Xiaochang,
Zhao Hongling,
Guan Hua,
Zhou Pingkun,
Gao Shanshan
Publication year - 2022
Publication title -
medcomm
Language(s) - English
Resource type - Journals
ISSN - 2688-2663
DOI - 10.1002/mco2.123
Subject(s) - dna damage , sumo protein , dna repair , dna pkcs , histone , chemistry , ku70 , comet assay , dna , microbiology and biotechnology , biology , biochemistry , ubiquitin , gene
The activation of DNA‐dependent kinase (DNA‐PKcs) upon DNA damage contains a cascade of reactions, covering acetylation by TIP60, binding with Ku70/80, and autophosphorylation. However, how cells regulate TIP60‐mediated acetylation of DNA‐PKcs and the following DNA‐PKcs activation upon DNA damage remains obscure. This present study reported that TIP60 is hyper‐SUMOylated in normal conditions, but upon irradiation‐induced DNA damage, small ubiquitin‐like modifier (SUMO)‐specific protease 3 (SENP3)‐mediated deSUMOylation of TIP60 promoted its interaction with DNA‐PKcs to form the TIP60‐DNA‐PKcs complex. We show that TIP60 SUMOylation is reduced quickly in response to DNA damage and the deSUMOylation of TIP60 by SENP3 is required for DNA‐PKcs acetylation and its autophosphorylation. Comet and γH2AX immunofluorescence assay showed that knockdown of SENP3 impaired DNA damage repair. Using the NHEJ report system, we found that knockdown of SENP3 affected the efficiency of NHEJ. Further exploration using clonogenic survival assay, cell viability assay and cytoflow assay suggested that leaking SENP3 increased the sensitivity of tumour cells to serval DNA damage treatment. Overall, our findings revealed a previously unidentified role of SENP3 in regulating DNA‐PKcs activity and DNA damage repair.

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