Preferential binding of human BRCA1 protein with open X-like conformation of Holliday junction, a homologous recombination intermediate
Kabir, S. H.; K, V.; Pal, N.
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BRCA1 is a complex tumor suppressor protein involved in multiple critical cellular processes, e.g., DNA double strand break repair, cell cycle checkpoint, etc. BRCA1 depleted cells are reported to have decreased homologous recombination (HR) and promote error-prone non-homologous end joining for DNA damage repair. Holliday junction (HJ) is an important intermediate of HR. Although BRCA1 is shown to have a very high affinity for HJ and recruits several proteins at the DNA damage site, the question remains what the binding mode of BRCA1 protein with an HJ is. Using single-molecule Fluorescence Correlation Spectroscopy (FCS) we have shown that BRCA1 prefers an open X-like conformation of HJ and has a lesser affinity for stacked HJ. Further, using molecular docking and all-atom molecular dynamics simulation, we show that mostly charged and polar amino acids in the DNA binding region of BRCA1 form complex with HJ. Interestingly, most of those amino acids are reported to be places for missense changes.
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