title: CtIP- and ATR-dependent FANCJ phosphorylation in response to DNA strand breaks mediated by DNA replication.
abstract: FANCJ, also called BACH1/BRIP1, is a 5'-3' DEAH helicase, whose mutations are known as a risk factor for Fanconi anemia and also breast and ovarian cancer. FANCJ is thought to contribute to DNA double-strand break (DSB) repair and S-phase checkpoint through binding to multiple partner proteins, such as BRCA1 and TopBP1, but its molecular regulation remains unclear. We focused on DNA damage-induced phosphorylation of FANCJ and found that reagents that cause DSB or replication fork stalling induce FANCJ hyperphosphorylation. In particular, camptothecin (CPT) induced rapid and efficient FANCJ hyperphosphorylation that was largely dependent on TopBP1 and ATM-Rad3 related (ATR) kinase. Furthermore, DNA end resection that exposes single-strand DNA at the DSB site was required for hyperphosphorylation. Interestingly, upon CPT treatment, a dramatic increase in the FANCJ-TopBP1 complex was observed, and this increase was not alleviated even when ATR-dependent hyperphosphorylation was suppressed. These results suggest that FANCJ function may be modulated by hyperphosphorylation in a DNA end resection- and ATR-dependent manner and by FANCJ-TopBP1 complex formation in response to replication-coupled DSBs.
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sakasai
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakai
authors.forename: Makoto
authors.initials: M
authors.lastname: Iimori
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiyonari
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kakeji
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitao
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002166:Camptothecin / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; D002166:Camptothecin