SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair
Abstract 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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-06-01
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| Series: | MedComm |
| Online Access: | https://doi.org/10.1002/mco2.123 |
| _version_ | 1818212289696759808 |
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| author | Yang Han Xin Huang Xiaoyu Cao Yuchen Li Lei Gao Jin Jia Gang Li Hejiang Guo Xiaochang Liu Hongling Zhao Hua Guan Pingkun Zhou Shanshan Gao |
| author_facet | Yang Han Xin Huang Xiaoyu Cao Yuchen Li Lei Gao Jin Jia Gang Li Hejiang Guo Xiaochang Liu Hongling Zhao Hua Guan Pingkun Zhou Shanshan Gao |
| author_sort | Yang Han |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T05:46:02Z |
| format | Article |
| id | doaj.art-86685675e8d74cb2b317f1bc628c85d5 |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-12-12T05:46:02Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-86685675e8d74cb2b317f1bc628c85d52022-12-22T00:35:48ZengWileyMedComm2688-26632022-06-0132n/an/a10.1002/mco2.123SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repairYang Han0Xin Huang1Xiaoyu Cao2Yuchen Li3Lei Gao4Jin Jia5Gang Li6Hejiang Guo7Xiaochang Liu8Hongling Zhao9Hua Guan10Pingkun Zhou11Shanshan Gao12Department of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaDepartment of Radiation Biology Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine Beijing ChinaAbstract 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.https://doi.org/10.1002/mco2.123 |
| spellingShingle | Yang Han Xin Huang Xiaoyu Cao Yuchen Li Lei Gao Jin Jia Gang Li Hejiang Guo Xiaochang Liu Hongling Zhao Hua Guan Pingkun Zhou Shanshan Gao SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair MedComm |
| title | SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair |
| title_full | SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair |
| title_fullStr | SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair |
| title_full_unstemmed | SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair |
| title_short | SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair |
| title_sort | senp3 mediated tip60 desumoylation is required for dna pkcs activity and dna damage repair |
| url | https://doi.org/10.1002/mco2.123 |
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