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 Wang; Zhongsheng You; Scott H. Kaufmann; Zhenkun Lou; Huadong Pei

doi:10.1038/ncomms10201

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 Wang, Zhongsheng You, Scott H. Kaufmann, Zhenkun LouHuadong Pei

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66 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 language	English (US)
Article number	10201
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10201
State	Published - Jan 5 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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., 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, Article 10201. https://doi.org/10.1038/ncomms10201

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, AA, Evans, DL, Kalari, KR, Zhang, P, Wang, L, You, Z, Kaufmann, SH , Lou, Z & Pei, H 2016, 'A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice', Nature communications, vol. 7, 10201. https://doi.org/10.1038/ncomms10201

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

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.",

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

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AU - Zhang, Haoxing

AU - Liu, Hailong

AU - Chen, Yali

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AU - Wang, Panfei

AU - Liu, Tongzheng

AU - Deng, Min

AU - Qin, Bo

AU - Correia, Cristina

AU - Lee, Seungbaek

AU - Kim, Jungjin

AU - Sparks, Melanie

AU - Nair, Asha A.

AU - Evans, Debra L.

AU - Kalari, Krishna R.

AU - Zhang, Pumin

AU - Wang, Liewei

AU - You, Zhongsheng

AU - Kaufmann, Scott H.

AU - Lou, Zhenkun

AU - Pei, Huadong

PY - 2016/1/5

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N2 - 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.

AB - 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.

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

Abstract

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