Ubiquitome Analysis Reveals PCNA-Associated Factor 15 (PAF15) as a Specific Ubiquitination Target of UHRF1 in Embryonic Stem Cells

Karg, Elisabeth; Smets, Martha; Ryan, Joël; Forné, Ignasi; Qin, Weihua; Mulholland, Christopher B.; Kalideris, Georgia; Imhof, Axel; Bultmann, Sebastian; Leonhardt, Heinrich

doi:10.1016/j.jmb.2017.10.014

Cited by 46 publications

(59 citation statements)

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“…PAF15 is important for maintenance of DNA methylation in mouse embryonic stem cells (mESCs). We had previously shown that murine UHRF1 (mUHRF1) ubiquitylates two neighboring lysines at the N-terminus of mPAF15 (K15 and K24) 36 with a similar spacing as in histone H3, suggesting a similar role in the recruitment of DNMT1 and the maintenance of DNA methylation in murine cells. To investigate the interaction between murine DNMT1 (mDNMT1) and mPAF15 and the role of ubiquitylation, we used CRISPR/Cas9-based gene editing to introduce K15R, K24R, or both K15R/K24R (KRKR) mutations into the endogenous Paf15 gene in mESCs ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…62 and Uhrf1 KO mESCs were described in ref. 36 . All mESC lines were maintained on 0.2% gelatin-coated dishes in Dulbecco's modified Eagle's medium (Sigma) supplemented with 16% fetal bovine serum (FBS, Sigma), 0.1 mM ß-mercaptoethanol (Invitrogen), 2 mM L-glutamine (Sigma), 1× Minimum Essential Medium nonessential amino acids (Sigma), 100 U/ml penicillin, 100 mg/ml streptomycin (Sigma), recombinant LIF (ESGRO, Millipore), and 2i (1 mM PD032591 and 3 mM CHIR99021 (Axon Medchem, Netherlands)).…”

Section: Methodsmentioning

confidence: 99%

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Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

et al. 2020

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Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual monoubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

et al. 2020

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“…The KIAA0101 protein contains a conserved PCNA‐binding motif and can compete for PCNA binding with the CDK inhibitor p21. UHRF1 ubiquitinates KIAA0101 and promotes its binding to PCNA during late S‐phase . KIAA0101 is involved in the regulation of various biological processes, such as DNA repair, cell cycle progression, and cell proliferation .…”

Section: Introductionmentioning

confidence: 99%

PCNA‐associated factor P15^PAF, targeted by FOXM1, predicts poor prognosis in high‐grade serous ovarian cancer patients

Jin

Liu

et al. 2018

Intl Journal of Cancer

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Activation of the FOXM1 signaling pathway and the PI3K/AKT/mTOR signaling pathway is associated with poor prognosis in ovarian cancer. In this study, we demonstrated that P15 (KIAA0101) was significantly upregulated in high-grade serous ovarian cancer (HGSOC) and that high KIAA0101 expression was associated with poor prognosis. FOXM1 transcriptionally activated KIAA0101 to drive proliferation and metastasis of ovarian cancer cells. KIAA0101 activated the PI3K/AKT/mTOR signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in ovarian cancer cells resulting in cisplatin resistance. Thus, KIAA0101 was closely related to the FOXM1 and PI3K/AKT/mTOR signaling pathways. Collectively, these findings provide insights into the mechanisms of poor prognosis of ovarian cancer and have implications for the development of both predictive and therapeutic biomarkers for the treatment of ovarian cancer.

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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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Ubiquitome Analysis Reveals PCNA-Associated Factor 15 (PAF15) as a Specific Ubiquitination Target of UHRF1 in Embryonic Stem Cells

Cited by 46 publications

References 46 publications

Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

PCNA‐associated factor P15^PAF, targeted by FOXM1, predicts poor prognosis in high‐grade serous ovarian cancer patients

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

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Ubiquitome Analysis Reveals PCNA-Associated Factor 15 (PAF15) as a Specific Ubiquitination Target of UHRF1 in Embryonic Stem Cells

Cited by 46 publications

References 46 publications

Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

PCNA‐associated factor P15PAF, targeted by FOXM1, predicts poor prognosis in high‐grade serous ovarian cancer patients

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

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PCNA‐associated factor P15^PAF, targeted by FOXM1, predicts poor prognosis in high‐grade serous ovarian cancer patients