title: RNF4 regulates DNA double-strand break repair in a cell cycle-dependent manner.
abstract: Both RNF4 and KAP1 play critical roles in the response to DNA double-strand breaks (DSBs), but the functional interplay of RNF4 and KAP1 in regulating DNA damage response remains unclear. We have previously demonstrated the recruitment and degradation of KAP1 by RNF4 require the phosphorylation of Ser824 (pS824) and SUMOylation of KAP1. In this report, we show the retention of DSB-induced pS824-KAP1 foci and RNF4 abundance are inversely correlated as cell cycle progresses. Following irradiation, pS824-KAP1 foci predominantly appear in the cyclin A (-) cells, whereas RNF4 level is suppressed in the G0-/G1-phases and then accumulates during S-/G2-phases. Notably, 53BP1 foci, but not BRCA1 foci, co-exist with pS824-KAP1 foci. Depletion of KAP1 yields opposite effect on the dynamics of 53BP1 and BRCA1 loading, favoring homologous recombination repair. In addition, we identify p97 is present in the RNF4-KAP1 interacting complex and the inhibition of p97 renders MCF7 breast cancer cells relatively more sensitive to DNA damage. Collectively, these findings suggest that combined effect of dynamic recruitment of RNF4 to KAP1 regulates the relative occupancy of 53BP1 and BRCA1 at DSB sites to direct DSB repair in a cell cycle-dependent manner.
authors.affiliation: a Department of Molecular Pharmacology , Beckman Research Institute, City of Hope , Duarte , CA , USA.|b Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute , City of Hope, Duarte , CA , USA.
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: a Department of Molecular Pharmacology , Beckman Research Institute, City of Hope , Duarte , CA , USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.affiliation: b Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute , City of Hope, Duarte , CA , USA.|c Department of Radiation Biology , Beckman Research Institute , City of Hope, Duarte , CA , USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
authors.affiliation: d Institute of Biomedical Sciences, Academia Sinica , Taipei , Taiwan , Republic of China.
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.affiliation: a Department of Molecular Pharmacology , Beckman Research Institute, City of Hope , Duarte , CA , USA.|b Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute , City of Hope, Duarte , CA , USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000528:radiation effects*; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000172:deficiency / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D021381:Protein Transport; D059767:Recombinational DNA Repair / Q000528:radiation effects; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D019925:Cyclin A; D009687:Nuclear Proteins; C114070:RNF4 protein, human; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D014157:Transcription Factors; D000071857:Tumor Suppressor p53-Binding Protein 1; C094680:nuclear protein import factor p97; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28
keywords: ATM; Cell cycle; DNA Damage Response; Homologous recombination repair; KAP1; RNF4; STUbL