HP1 regulates the localization of FANCJ at sites of DNA double-strand breaks.
The breast and ovarian cancer predisposition protein BRCA1 forms three mutually exclusive complexes with Fanconi anemia group J protein (FANCJ, also called BACH1 or BRIP1), CtIP, and Abraxas/RAP80 through its BRCA1 C terminus (BRCT) domains, while its RING domain binds to BRCA1-associated RING domain 1 (BARD1). We recently found that ... the interaction between heterochromatin protein 1 (HP1) and BARD1 is required for the accumulation of BRCA1 and CtIP at sites of DNA double-strand breaks. Here, we investigated the importance of HP1 and BARD1-HP1 interaction in the localization of FANCJ together with the other BRCA1-BRCT binding proteins to clarify the separate role of the HP1-mediated pathway from the RNF8/RNF168-induced ubiquitin-mediated pathway for BRCA1 function. FANCJ interacts with HP1γ in a BARD1-dependent manner, and this interaction was enhanced by ionizing radiation or irinotecan hydrochloride treatment. Simultaneous depletion of all three HP1 isoforms with shRNAs disrupts the accumulation of FANCJ and CtIP, but not RAP80, at double-strand break sites. Replacement of endogenous BARD1 with a mutant BARD1 that is incapable of binding to HP1 also disrupts the accumulation of FANCJ and CtIP, but not RAP80. In contrast, RNF168 depletion disrupts the accumulation of only RAP80, but not FANCJ or CtIP. Consequently, the accumulation of conjugated ubiquitin was only inhibited by RNF168 depletion, whereas the accumulation of RAD51 and sister chromatid exchange were only inhibited by HP1 depletion or disruption of the BARD1-HP1 interaction. Taken together, the results suggest that the BRCA1-FANCJ and BRCA1-CtIP complexes are not downstream of the RNF8/RNF168/ubiquitin pathway, but are instead regulated by the HP1 pathway that precedes homologous recombination DNA repair.
Mesh Terms:
Basic-Leucine Zipper Transcription Factors, Carrier Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Fanconi Anemia Complementation Group Proteins, HeLa Cells, Humans, Models, Biological, Nuclear Proteins, Protein Binding, Rad51 Recombinase, Sister Chromatid Exchange, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases
Basic-Leucine Zipper Transcription Factors, Carrier Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Fanconi Anemia Complementation Group Proteins, HeLa Cells, Humans, Models, Biological, Nuclear Proteins, Protein Binding, Rad51 Recombinase, Sister Chromatid Exchange, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases
Cancer Sci.
Date: Oct. 01, 2016
PubMed ID: 27399284
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