A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice

Haoxing Zhang, Hailong Liu, Yali Chen, Xu Yang, Panfei Wang, Tongzheng Liu, Min Deng, Bo Qin, Cristina Correia, Seungbaek Lee, Jungjin Kim, Melanie Sparks, Asha A. Nair, Debra L. Evans, Krishna R Kalari, Pumin Zhang, Liewei M Wang, Zhongsheng You, Scott H Kaufmann, Zhenkun LouHuadong Pei

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Article number10201
JournalNature Communications
Volume7
DOIs
StatePublished - Jan 5 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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    Zhang, H., Liu, H., Chen, Y., Yang, X., Wang, P., Liu, T., Deng, M., Qin, B., Correia, C., Lee, S., Kim, J., Sparks, M., Nair, A. A., Evans, D. L., Kalari, K. R., Zhang, P., Wang, L. M., You, Z., Kaufmann, S. H., ... Pei, H. (2016). A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nature Communications, 7, [10201]. https://doi.org/10.1038/ncomms10201