A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26727879.
- Also identified by DOI 10.1038/ncomms10201 and PMC identifier 4728409.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- BRCA1 Protein
- CCAAT-Enhancer-Binding Proteins
- DNA Breaks, Double-Stranded
- DNA Repair