APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage

Cotto-Rios, Xiomaris M.; Ma, Jones; Busino, Luca; Pagano, Michele; Huang, Tony T.

doi:10.1083/jcb.201101062

Cited by 65 publications

(80 citation statements)

References 56 publications

(79 reference statements)

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“…1 USP1 protein levels are downregulated during the G 1 phase, begin to accumulate as cells entered S phase and remain elevated until the late stages of mitosis. 33,34 To examine whether loss of Usp1 function can cause a defect in centrosome duplication during S phase, we measured the centrosome number from immortalized Usp1 C/C and Usp1 ¡/¡ MEFs ( Fig. 2A-C).…”

Section: Usp1 Ablation Delays Centrosome Duplicationmentioning

confidence: 99%

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

2016

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Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting chromosome missegregation. Therefore, maintenance of accurate centrosome number is critical for cell fate. The deubiquitinating enzyme USP1 plays important roles in DNA repair and cell differentiation. Importantly, increased levels of USP1 are detected in certain types of human cancer, but little is known about the significance of USP1 overexpression in cancer development. Here we show that Usp1 plays a novel role in regulating centrosome duplication. The ectopic expression of wild-type Usp1, but not C90S Usp1 (catalytically inactive mutant form), induced centrosome amplification. Conversely, ablation of Usp1 in mouse embryonic fibroblasts (MEFs) showed a significant delay in centrosome duplication. Moreover, Usp1-induced centrosome amplification caused abnormal mitotic spindles, chromosome missegregation and aneuploidy. Interestingly, loss of inhibitor of DNA binding protein 1 (ID1) suppressed Usp1-induced centrosome amplification. Taken together, our results strongly suggest that Usp1 is involved in the regulation of centrosome duplication, at least in part via ID1, and Usp1 may exert its oncogenic activity, partially through inducing centrosome abnormality.

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Section: Usp1 Ablation Delays Centrosome Duplicationmentioning

confidence: 99%

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

2016

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“…Deubiquitinases (DUB), which include over 100 genes classified into five subgroups, catalyze the removal of ubiquitin molecules that are covalently bound to a substrate, thus diminishing its proteasomal degradation (17). Recent work has identified a role for USP1, a member of the ubiquitin-specific peptidase (USP) group of DUBs, in the regulation of tumor pathogenesis (19)(20)(21) including glioblastoma (22). Inhibition of USP1 by multiple strategies has been suggested as a potential strategy to enhance the therapeutic efficacy of chemotherapy and radiation in treating cancer (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

et al. 2016

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Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1. Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling.

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“…One example is ubiquitin-specific protease 1, in which three putative D box and KEN box sequences are found to be irrelevant to protein stability. 60 We have also searched the REV1 sequence for other APC substrate recognition motifs, including A-box, 38 CRY box, 39 GxEN box, 61 O box 62 and TEK box, 63 but none is present. In some proteins targeted by APC, as long as the conserved arginine and leucine residues in a relaxed version of the D box 3-5); a plasmid expressing an irrelevant control shRNa (shCtrl) was used as a negative control.…”

Section: Apc-mediated Degradation Of Rev1mentioning

confidence: 99%

REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1

2013

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APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage

Abstract: APC/CCdh1-dependent degradation of USP1 allows for PCNA monoubiquitination and subsequent recruitment of trans-lesion synthesis polymerase to UV repair sites.

Cited by 65 publications

References 56 publications

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1

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