USP48 restrains resection by site-specific cleavage of the BRCA1 ubiquitin mark from H2A

Uckelmann, Michael; Densham, Ruth M; Baas, Roy; Winterwerp, H.H.K.; Fish, Alexander; Sixma, Titia K.; Morris, Joanna R.

doi:10.1038/s41467-017-02653-3

Cited by 86 publications

(94 citation statements)

References 64 publications

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“…We show that USP1 specifically targets one ubiquitinated lysine made by a specific E3 ligase, FANCL. Another DUB, USP48, was recently published to also specifically oppose the monoubiquitination made by another lysine specific E3 ligase BRCA1 26 . This suggests that some DUBs and E3 activities may have co-evolved to oppose each other on specific cellular signals and maintain an appropriate equilibrium of non-ubiquitinated and ubiquitinated substrate.…”

Section: Discussionmentioning

confidence: 99%

“…To date most of our understanding of DUB specificity has used ubiquitin-ubiquitin linkages as substrates, likely due to the advances in purifying large quantities of ubiquitin chains. However, there are few examples of studies which have used monoubiquitinated substrates with a native isopeptide, and these include PCNA-Ub 25 and histones 26 . Particularly in the case of histone H2A and H2B, the generation of monoubiquitinated substrates has facilitated the elucidation of the mechanisms of substrate targeting by histone-specific DUBs 26,27 .…”

Section: Introductionmentioning

confidence: 99%

“…However, there are few examples of studies which have used monoubiquitinated substrates with a native isopeptide, and these include PCNA-Ub 25 and histones 26 . Particularly in the case of histone H2A and H2B, the generation of monoubiquitinated substrates has facilitated the elucidation of the mechanisms of substrate targeting by histone-specific DUBs 26,27 . The ability to make physiological substrates allows for a modular approach to understanding the requirements for specificity and how DUBs such as USP1 work at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

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Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1

Arkinson

Chaugule

Toth

et al. 2018

Preprint

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The DNA damage response depends on ubiquitin signalling to orchestrate DNA repair. The Fanconi Anemia pathway for interstrand crosslink repair, and the translesion synthesis pathway for DNA damage tolerance, both require cycles of monoubiquitination and deubiquitination. The ubiquitin specific protease USP1 regulates both these pathways by deubiquitinating monoubiquitinated PCNA, FANCD2 and FANCI. Loss of USP1 activity gives rise to chromosomal instability.While many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitinsubstrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here we show that the molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We find that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1

Arkinson

Chaugule

Toth

et al. 2018

Preprint

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“…USP48 promotes genomic stability by antagonizing the BRCA1 E3 ligase function. Depletion of USP48 increases the distance between p53-binding protein 1 (53BP1) from the DNA break point [77]. It should be noted that histone ubiquitination by RNF168 is a critical event for the recruitment of BRCA1 and 53BP1, and the stability of RNF168 can be regulated by USP7.…”

Section: Dubs and The Ddrmentioning

confidence: 99%

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

Lai

Chen

Tse

2020

IJMS

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Deubiquitinases (DUBs) are involved in various cellular functions. They deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. Studies on the roles of deubiquitylation have been conducted in various cancers to identify the carcinogenic roles of DUBs. In this review, we evaluate the biological roles of DUBs in cancer, including proliferation, cell cycle control, apoptosis, the DNA damage response, tumor suppression, oncogenesis, and metastasis. This review mainly focuses on the regulation of different downstream effectors and pathways via biochemical regulation and posttranslational modifications. We summarize the relationship between DUBs and human cancers and discuss the potential of DUBs as therapeutic targets for cancer treatment. This review also provides basic knowledge of DUBs in the development of cancers and highlights the importance of DUBs in cancer biology.

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“…Recombinant human PCNA was purified and ubiquitinated enzymatically as described previously (Hibbert and Sixma, 2012). Recombinant nucleosomes enzymatically ubiquitinated at histone H2A-K13/15 by RNF168 and H2A-K125/127129 by BRCA1-BARD1 (Zhu et al, 2011;Mattiroli et al, 2012Kalb et al, 2014;Uckelmann et al, 2018;Dharadhar et al, 2019;Horn et al, 2019) were included as controls (Figures 6A-C). Among the analyzed clones we observed antibodies recognizing PCNA and Ub alone.…”

Section: Validation Of the Antibodymentioning

confidence: 99%

Strategy for Development of Site-Specific Ubiquitin Antibodies

et al. 2020

Self Cite

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Protein ubiquitination is a key post-translational modification regulating a wide range of biological processes. Ubiquitination involves the covalent attachment of the small protein ubiquitin to a lysine of a protein substrate. In addition to its well-established role in protein degradation, protein ubiquitination plays a role in protein-protein interactions, DNA repair, transcriptional regulation, and other cellular functions. Understanding the mechanisms and functional relevance of ubiquitin as a signaling system requires the generation of antibodies or alternative reagents that specifically detect ubiquitin in a site-specific manner. However, in contrast to other post-translational modifications such as acetylation, phosphorylation, and methylation, the instability and size of ubiquitin−76 amino acids-complicate the preparation of suitable antigens and the generation antibodies detecting such site-specific modifications. As a result, the field of ubiquitin research has limited access to specific antibodies. This severely hampers progress in understanding the regulation and function of site-specific ubiquitination in many areas of biology, specifically in epigenetics and cancer. Therefore, there is a high demand for antibodies recognizing site-specific ubiquitin modifications. Here we describe a strategy for the development of site-specific ubiquitin antibodies. Based on a recently developed antibody against site-specific ubiquitination of histone H2B, we provide detailed protocols for chemical synthesis methods for antigen preparation and discuss considerations for screening and quality control experiments.

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USP48 restrains resection by site-specific cleavage of the BRCA1 ubiquitin mark from H2A

Cited by 86 publications

References 64 publications

Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1

Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

Strategy for Development of Site-Specific Ubiquitin Antibodies

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