Abstract
BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. Subsequently, UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. Thus, UHRF1 is a key regulator of DSB repair choice, which is separate from its role in heterochromatin formation and epigenetic regulator.
Highlights
BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase
As UHRF1 interacts with BRCA1 in S phase and induces RIF1 ubiquitination after ionizing radiation (IR), we asked whether UHRF1-mediated RIF1 ubiquitination was important for the regulation of RIF1 accumulation at double-strand breaks (DSBs)
RIF1 acts as a key factor in the regulation of DSB repair pathway choice
Summary
BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. Nonhomologous end joining (NHEJ) and homologous recombination (HR) are two key pathways that mediate the repair of DSBs1–4. Initiation of these processes is tightly regulated, and aberrant pathway activation results in genomic instability[5,6,7,8,9]. How UHRF1 functions in the DNA repair choice remains unclear
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