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首页> 中文期刊> 《癌症生物学与医学：英文版》 >Kinetochore protein MAD1 participates in the DNA damage response through ataxia-telangiectasia mutated kinase-mediated phosphorylation and enhanced interaction with KU80

Kinetochore protein MAD1 participates in the DNA damage response through ataxia-telangiectasia mutated kinase-mediated phosphorylation and enhanced interaction with KU80

         
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摘要

Objective:Mitotic arrest-deficient protein 1(MAD1)is a kinetochore protein essential for the mitotic spindle checkpoint.Proteomic studies have indicated that MAD1 is a component of the DNA damage response(DDR)pathway.However,whether and how MAD1 might be directly involved in the DDR is largely unknown.Methods:We ectopically expressed the wild type,or a phosphorylation-site--mutated form of MAD1 in MAD1 knockdown cells to look for complementation effects.We used the comet assay,colony formation assay,immunofluorescence staining,and flow cytometry to assess the DDR,radiosensitivity,and the G2/M checkpoint.We employed co-immunoprecipitation followed by mass spectrometry to identify MAD1 interacting proteins.Data were analyzed using the unpaired Student''st-test.Results:We showed that MAD1 was required for an optimal DDR,as knocking down MAD1 resulted in impaired DNA repair and hypersensitivity to ionizing radiation(IR).We found that IR-induced serine 214 phosphorylation was ataxia-telangiectasia mutated(ATM)kinase-dependent.Mutation of serine 214 to alanine failed to rescue the phenotypes of MAD1 knockdown cells in response to IR.Using mass spectrometry,we identified a protein complex mediated by MAD1 serine 214 phosphorylation in response to IR.Among them,we showed that KU80 was a key protein that displayed enhanced interaction with MAD1 after DNA damage.Finally,we showed that MAD1 interaction with KU80 required serine 214 phosphorylation,and it was essential for activation of DNA protein kinases catalytic subunit(DNA-PKcs).Conclusions:MAD1 serine 214 phosphorylation mediated by ATM kinase in response to IR was required for the interaction with KU80 and activation of DNA-PKCs.

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  • 来源
    《癌症生物学与医学：英文版》 |2020年第3期|P.640-651|共12页
  • 作者

    Mingming Xiao; Xuesong Li; Yang Su; Zhuang Liu; Yamei Han; Shuai Wang; Qinghua Zeng; Hong Liu; Jianwei Hao; Bo Xu;

  • 作者单位

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Oncology Southern Research Institute Birmingham AL 35205 USA;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 China;

    Department of Neurosurgery Tianjin Huanhu Hospital Tianjin 300350 ChinaTianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases Tianjin 300350 China;

    Department of Biochemistry and Molecular Biology Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin''s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Oncology Southern Research Institute Birmingham AL 35205 USACenter for Intelligent Oncology Chongqing University Cancer Hospital Chongqing University School of Medicine Chongqing 400030 China;

  • 原文格式 PDF
  • 正文语种 chi
  • 中图分类 计算技术、计算机技术;
  • 关键词

    DNA damage response; ataxia-telangiectasia mutated kinase(ATM); mitotic arrest-deficient protein 1(MAD1); KU80 protein; DNA-PKcs;

    机译：DNA损伤反应;共济失调 - 卵巢突变激酶（ATM）;有丝分裂抑制蛋白1（MAD1）;KU80蛋白;DNA-PKCS;
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