title: BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1.
abstract: DNA damage response (DDR) and the centrosome cycle are 2 of the most critical cellular processes affecting the genome stability in animal cells. Yet the cross-talks between DDR and the centrosome are poorly understood. Here we showed that deficiency of the breast cancer 1, early onset gene (BRCA1) induces centrosome amplification in non-stressed cells as previously reported while attenuating DNA damage-induced centrosome amplification (DDICA) in cells experiencing prolonged genotoxic stress. Mechanistically, the function of BRCA1 in promoting DDICA is through binding and recruiting polo-like kinase 1 (PLK1) to the centrosome. In a recent study, we showed that FancJ also suppresses centrosome amplification in non-stressed cells while promoting DDICA in both hydroxyurea and mitomycin C treated cells. FancJ is a key component of the BRCA1 B-complex. Here, we further demonstrated that, in coordination with BRCA1, FancJ promotes DDICA by recruiting both BRCA1 and PLK1 to the centrosome in the DNA damaged cells. Thus, we have uncovered a novel role of BRCA1 and FancJ in the regulation of DDICA. Dysregulation of DDR or centrosome cycle leads to aneuploidy, which is frequently seen in both solid and hematological cancers. BRCA1 and FancJ are known tumor suppressors and have well-recognized functions in DNA damage checkpoint and DNA repair. Together with our recent findings, we demonstrated here that BRCA1 and FancJ also play an important role in centrosome cycle especially in DDICA. DDICA is thought to be an alternative fail-safe mechanism to prevent cells experiencing severe DNA damage from becoming carcinogenic. Therefore, BRCA1 and FancJ are potential liaisons linking early DDR with the DDICA. We propose that together with their functions in DDR, the role of BRCA1 and FancJ in the activation of DDICA is also crucial for their tumor suppression functions in vivo.
authors.affiliation: a Basic Biomedical Science Division; Sanford School of Medicine ; University of South Dakota ; Vermillion , SD USA.
authors.forename: Jianqiu
authors.initials: J
authors.lastname: Zou
authors.forename: Deli
authors.initials: D
authors.lastname: Zhang
authors.forename: Guang
authors.initials: G
authors.lastname: Qin
authors.forename: Xiangming
authors.initials: X
authors.lastname: Chen
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D019313:BRCA1 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C102108:BACH1 protein, human; C492913:BRCA1 protein, human
keywords: ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia Rad3-related; BRCA1; BRCA1, breast cancer gene 1; CIN, chromosome instability; DDICA, DNA damage induced centrosome amplification; DDR, DNA damage response; DNA damage response; FancJ; GFP, green fluorescent protein; HR, homologous recombination; HU, hydroxyurea; ICL, interstrand cross-linkers; MIN, microsatellite instability; MMC, mitomycin C; MT, microtubule; PCM, pericentriolar materials; PLK1; PLK1, Polo-like kinase 1; UTR, untranslated region; WCL, whole-cell lysate; centrosome amplification; interstrand cross-link