CtIP- and ATR-dependent FANCJ phosphorylation in response to DNA strand breaks mediated by DNA replication.

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.
Mesh Terms:
Ataxia Telangiectasia Mutated Proteins, Basic-Leucine Zipper Transcription Factors, Camptothecin, Carrier Proteins, Cell Cycle Proteins, DNA Breaks, Double-Stranded, DNA Breaks, Single-Stranded, DNA Damage, DNA Replication, DNA-Binding Proteins, Fanconi Anemia Complementation Group Proteins, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, Protein-Serine-Threonine Kinases
Genes Cells
Date: Dec. 01, 2012
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