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

Zhang, Haoxing; Liu, Hailong; Chen, Yali; Xu, Yang; Wang, Panfei; Liu, Tongzheng; Deng, Min; Qin, Bo; Correia, Cristina; Lee, SeungBaek; Kim, Jung-Jin; Sparks, Melanie; Nair, Asha; Evans, Debra L.; Kalari, Krishna R.; Zhang, Pumin; Wang, Liewei M; You, Zhipeng; Kaufmann, Scott H.; Lou, Zhenkun; Pei, Huadong

doi:10.1038/ncomms10201

Cited by 107 publications

(129 citation statements)

References 69 publications

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“…Recent studies demonstrated that the function of UHRF1 in DNA repair is independent of its role in epigenetic regulation and identified a role for UHRF1 in regulating replication block bypass via PCNA-associated factor 15 (PAF15) ubiquitination (39,40). The Uhrf1 Zp3 cKO GV oocytes and 2-cell embryos displayed abundant nuclear g-H2AX signals compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Deletion of maternal UHRF1 severely reduces mouse oocyte quality and causes developmental defects in preimplantation embryos

Cao

Liu

et al. 2019

FASEB j.

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The ubiquitin‐like, containing PHD and RING finger domains, 1 (UHRF1) protein recognizes DNA methylation and histone modification and plays a critical role in epigenetic regulation. Recently, UHRF1 was shown to have a role in DNA methylation in oocytes and early embryos. Here, we reveal that maternal UHRF1 determines the quality of mouse oocytes. We generated oocyte‐specific Uhrf1‐knockout mice and found that females were sterile, and few maternal UHRF1‐null embryos developed into blastocysts. The UHRF1‐null oocytes had an increased incidence of aneuploidy and DNA damage. In addition to defective DNA methylation, histone modification was affected during oogenesis, with UHRF1‐null germinal vesicle and metaphase II‐stage oocytes exhibiting reduced global histone H3 lysine 9 dimethylation levels and elevated acetylation of histone H4 lysine 12. Taken together, our results suggest that UHRF1 plays an important role in determining oocyte quality and affects epigenetic regulation of oocyte maturation as a maternal protein, which is crucial for embryo developmental potential. Further exploration of the biologic function and underlying mechanisms of maternal UHRF1 will enhance our understanding of the maternal control of the oocyte and early embryonic development.—Cao, Y., Li, M., Liu, F., Ni, X., Wang, S., Zhang, H., Sui, X., Huo, R. Deletion of maternal UHRF1 severely reduces mouse oocyte quality and causes developmental defects in preimplantation embryos. FASEB J. 33, 8294–8305 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Deletion of maternal UHRF1 severely reduces mouse oocyte quality and causes developmental defects in preimplantation embryos

Cao

Liu

et al. 2019

FASEB j.

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“…Subsequent dissociation of RIF1 from 53BP1, an antagonized effector of BRCA1, resulted in inhibition of NHEJ repair system and thus initiation of homologous recombination. 70 Involvement of UHRF1 in double-strand repair pathway was also shown in esophageal squamous cell carcinoma, where inhibition of UHRF1 downregulated endogenous levels of Ku heterodimer protein complex (Ku70/Ku80) which is well known to catalyze NHEJ DNA repair. 71 …”

Section: Involvement Of Uhrf1 In Dna Repairmentioning

confidence: 96%

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Sidhu

Capalash

2017

Tumour Biol.

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UHRF1 is a master regulator of epigenome as it coordinates DNA methylation and histone modifications. Compelling evidence suggests a strong link between UHRF1 overexpression and tumorigenesis, substantiating its ability to act as a potential biomarker for cancer diagnosis and prognosis. UHRF1 also mediates repair of damaged DNA that makes cancer cells resistant toward cytocidal drugs. Hence, understanding the molecular mechanism of UHRF1 regulation would help in developing cancer therapeutics. Natural compounds have shown applicability to downregulate UHRF1 leading to growth arrest and apoptosis in cancer cells.

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“…For example, BRCA1 disrupts the interaction of 53BP1 and RIF1 in S/G2 phases by promoting dephosphorylation of 53BP1 by the PP4C phosphatase and targeting RIF1 by an E3 ubiquitin ligase UHRF1 (Isono et al 2017, Zhang et al 2016). BRCA1 also induces the exclusion of 53BP1 from the core of DNA damage foci in S/G2 phases (Chapman et al 2012a, Kakarougkas et al 2013).…”

Section: Brca1 Regulates End Resection–dependent Double-strand Brementioning

confidence: 99%

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

Chen

Feng

Lim

et al. 2018

Annu. Rev. Cancer Biol.

258

221

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Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

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

Cited by 107 publications

References 69 publications

Deletion of maternal UHRF1 severely reduces mouse oocyte quality and causes developmental defects in preimplantation embryos

Deletion of maternal UHRF1 severely reduces mouse oocyte quality and causes developmental defects in preimplantation embryos

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

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