title: Roles of Kruppel-associated Box (KRAB)-associated Co-repressor KAP1 Ser-473 Phosphorylation in DNA Damage Response.
abstract: The Kruppel-associated box (KRAB)-associated co-repressor KAP1 is an essential nuclear co-repressor for the KRAB zinc finger protein superfamily of transcriptional factors. Ataxia telangiectasia mutated (ATM)-Chk2 and ATM- and Rad3-related (ATR)-Chk1 are two primary kinase signaling cascades activated in response to DNA damage. A growing body of evidence suggests that ATM and ATR phosphorylate KAP1 at Ser-824 in response to DNA damage and regulate KAP1-dependent chromatin condensation, DNA repair, and gene expression. Here, we show that, depending on the type of DNA damage that occurs, KAP1 Ser-473 can be phosphorylated by ATM-Chk2 or ATR-Chk1 kinases. Phosphorylation of KAP1 at Ser-473 attenuated its binding to the heterochromatin protein 1 family proteins and inhibited its transcriptional repression of KRAB-zinc finger protein (KRAB-ZFP) target genes. Moreover, KAP1 Ser-473 phosphorylation induced by DNA damage stimulated KAP1-E2F1 binding. Overexpression of heterochromatin protein 1 significantly inhibited E2F1-KAP1 binding. Elimination of KAP1 Ser-473 phosphorylation increased E2F1-targeted proapoptotic gene expression and E2F1-induced apoptosis in response to DNA damage. Furthermore, loss of phosphorylation of KAP1 Ser-473 led to less BRCA1 focus formation and slower kinetics of loss of γH2AX foci after DNA damage. KAP1 Ser-473 phosphorylation was required for efficient DNA repair and cell survival in response to DNA damage. Our studies reveal novel functions of KAP1 Ser-473 phosphorylation under stress.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and College of Life Science and.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.forename: Shengping
authors.initials: S
authors.lastname: Zhang
authors.forename: Xuan
authors.initials: X
authors.lastname: Gao
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Gao
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Xu
authors.forename: Ya
authors.initials: Y
authors.lastname: Lv
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Zhu
authors.forename: Changqing
authors.initials: C
authors.lastname: Zhang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
authors.forename: Yongping
authors.initials: Y
authors.lastname: Cui
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D042002:Chromatin Assembly and Disassembly; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D012694:Serine; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases