Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRCC36 is a member of the JAMM/MPN(+) family of zinc metalloproteases that specifically cleaves Lys 63-linked polyubiquitin chains in vitro. We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. This complex participates in the regulation of BRCA1 localization in response to DNA damage. Here we provide evidence indicating that BRCC36 regulates the abundance of Lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone H2A. Moreover, besides interacting with CCDC98 within the BRCA1-A complex, BRCC36 also associates with another protein KIAA0157, which shares significant sequence homology with CCDC98. Interestingly, although CCDC98 functions as an adaptor of BRCC36 and regulates BRCC36 activity in the nucleus, KIAA0157 mainly localizes in cytosol and activates BRCC36 in the cytoplasm. Moreover, these two complexes appear to exist in fine balance in vivo because reduction of KIAA0157 expression led to an increase of the BRCA1-A complex in the nucleus. Together, these results suggest that scaffold proteins not only participate in the regulation of BRCC36 activity but also determine its subcellular localization and cellular functions.
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PMID:The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments. 2065 90

Ubiquitin pathway E3 ligases are an important component conferring specificity and regulation in ubiquitin attachment to substrate proteins. The Arabidopsis thaliana RING (Really Interesting New Gene) domain-containing proteins BRIZ1 and BRIZ2 are essential for normal seed germination and post-germination growth. Loss of either BRIZ1 (At2g42160) or BRIZ2 (At2g26000) results in a severe phenotype. Heterozygous parents produce progeny that segregate 3:1 for wild-type:growth-arrested seedlings. Homozygous T-DNA insertion lines are recovered for BRIZ1 and BRIZ2 after introduction of a transgene containing the respective coding sequence, demonstrating that disruption of BRIZ1 or BRIZ2 in the T-DNA insertion lines is responsible for the observed phenotype. Both proteins have multiple predicted domains in addition to the RING domain as follows: a BRAP2 (BRCA1-Associated Protein 2), a ZnF UBP (Zinc Finger Ubiquitin Binding protein), and a coiled-coil domain. In vitro, both BRIZ1 and BRIZ2 are active as E3 ligases but only BRIZ2 binds ubiquitin. In vitro synthesized and purified recombinant BRIZ1 and BRIZ2 preferentially form hetero-oligomers rather than homo-oligomers, and the coiled-coil domain is necessary and sufficient for this interaction. BRIZ1 and BRIZ2 co-purify after expression in tobacco leaves, which also requires the coiled-coil domain. BRIZ1 and BRIZ2 coding regions with substitutions in the RING domain are inactive in vitro and, after introduction, fail to complement their respective mutant lines. In our current model, BRIZ1 and BRIZ2 together are required for formation of a functional ubiquitin E3 ligase in vivo, and this complex is required for germination and early seedling growth.
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PMID:BRIZ1 and BRIZ2 proteins form a heteromeric E3 ligase complex required for seed germination and post-germination growth in Arabidopsis thaliana. 2081 Jun 61

: DNA double-strand breaks (DSBs) are extremely cytotoxic with a single unrepaired DSB being sufficient to induce cell death. A complex signalling cascade, termed the DNA damage response (DDR), is in place to deal with such DNA lesions and maintain genome stability. Recent work by us and others has found that the signalling cascade activated by DSBs in mitosis is truncated, displaying apical, but not downstream, components of the DDR. The E3 Ubiquitin ligases RNF8, RNF168 and BRCA1, along with the DDR mediator 53BP1, are not recruited to DSB sites in mitosis, and activation of downstream checkpoint kinases is also impaired. Here, we show that RNF8 and RNF168 are recruited to DNA damage foci in late mitosis, presumably to prime sites for 53BP1 recruitment in early G1. Interestingly, we show that, although RNF8, RNF168 and 53BP1 are excluded from DSB sites during most of mitosis, they associate with mitotic structures such as the kinetochore, suggesting roles for these DDR factors during mitotic cell division. We discuss these and other recent findings and suggest how these novel data collectively contribute to our understanding of mitosis and how cells deal with DNA damage during this crucial cell cycle stage.
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PMID:Give me a break, but not in mitosis: the mitotic DNA damage response marks DNA double-strand breaks with early signaling events. 2141 56

Over-expressed in numerous cancers, Ubiquitin-like containing PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) is characterized by a SRA domain (Set and Ring Associated) which is found only in the UHRF family. UHRF1 constitutes a complex with histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) via its SRA domain and represses the expression of several tumour suppressor genes (TSGs) including p16INK4A, hMLH1, BRCA1 and RB1. Conversely, UHRF1 is regulated by other TSGs such as p53 and p73. UHRF1 is hypothetically involved in a macro-molecular protein complex called "ECREM" for "Epigenetic Code Replication Machinery". This complex would be able to duplicate the epigenetic code by acting at the DNA replication fork and by activating the right enzymatic activity at the right moment. There are increasing evidence that UHRF1 is the conductor of this replication process by ensuring the crosstalk between DNA methylation and histone modifications via the SRA and Tandem Tudor Domains, respectively. This cross-talk allows cancer cells to maintain the repression of TSGs during cell proliferation. Several studies showed that down-regulation of UHRF1 expression in cancer cells by natural pharmacological active compounds, favors enhanced expression or re-expression of TSGs, suppresses cell growth and induces apoptosis. This suggests that hindering UHRF1 to exert its role in the duplication of the methylation patterns (DNA + histones) is responsible for inducing apoptosis. In this review, we present UHRF1 expression as a target of several natural products and we discuss their underlying molecular mechanisms and benefits for chemoprevention and chemotherapy.
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PMID:Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. 2149 37

Impairment of homologous recombination (HR), a vital process employed during repair of DNA double strand breaks and stalled DNA replication, provides a valuable opportunity for the cell to become transformed. Once transformed, the impairment turns to be a target for therapy as exemplified by the synthetic lethal strategy such as poly (ADP-ribose) polymerase (PARP) inhibitor for BRCA1/2-defective breast and ovarian cancer. Hence, improving mechanistic understanding of HR has emerged as an urgent issue to address due to the high clinical demand. Ubiquitin modification plays a central role in HR and more than a few E3 ubiquitin ligases have been implicated in the process. However, the significance of the activity of one such key E3 ligase, BRCA1, has not yet been clarified and remains as a major obstacle in the field. Here, we review recent advances in our understanding of BRCA1 function in HR and discuss possible roles of the activity.
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PMID:The BRCA1 ubiquitin ligase and homologous recombination repair. 2157 Sep 76

RAP80 (receptor-associated protein 80) is a ubiquitin-binding protein that can specifically recognize and bind to Lys-63-linked polyubiquitin chains, thus targeting the BRCA1-A complex to DNA damage sites. To study the role of RAP80 in vivo, we generated RAP80-deficient mice. The deficient mice are prone to B-cell lymphomagenesis. B-cell lymphomas in RAP80-deficient mice are nearly diploid but harbor clonal chromosome translocations. Moreover, the deficient mice are hypersensitive to ionizing radiation. Repair of ionizing radiation-induced DNA double-strand breaks is impaired in RAP80-deficient mouse embryonic fibroblasts. Mechanistically, loss of RAP80 suppresses recruitment of the BRCA1-A complex to DNA damage sites and abrogates the DNA damage repair process at DNA damage sites. Taken together, these results reveal that RAP80 plays a crucial role in the DNA damage response and in maintaining genomic integrity.
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PMID:RAP80 protein is important for genomic stability and is required for stabilizing BRCA1-A complex at DNA damage sites in vivo. 2253 52

Ubiquitin (Ub) modifications at sites of DNA double-strand breaks (DSBs) play critical roles in the assembly of signaling and repair proteins. The Ub-interacting motif (UIM) domain of Rap80, which is a component of the BRCA1-A complex, interacts with Ub Lys-63 linkage conjugates and mediates the recruitment of BRCA1 to DSBs. Small ubiquitin-like modifier (SUMO) conjugation also occurs at DSBs and promotes Ub-dependent recruitment of BRCA1, but its molecular basis is not clear. In this study, we identified that Rap80 possesses a SUMO-interacting motif (SIM), capable of binding specifically to SUMO2/3 conjugates, and forms a tandem SIM-UIM-UIM motif at its N terminus. The SIM-UIM-UIM motif binds to both Ub Lys-63 linkage and SUMO2 conjugates. Both the SIM and UIM domains are required for efficient recruitment of Rap80 to DSBs immediately after damage and confer cellular resistance to ionizing radiation. These findings propose a model in which SUMO and Ub modification is coordinated to recruit Rap80 and BRCA1 to DNA damage sites.
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PMID:Rap80 protein recruitment to DNA double-strand breaks requires binding to both small ubiquitin-like modifier (SUMO) and ubiquitin conjugates. 2268 73

Breast cancer is the most common malignancy in women and a significant cause of morbidity and mortality. Sub-types of breast cancer defined by the expression of steroid hormones and Her2/Neu oncogene have distinct prognosis and undergo different therapies. Besides differing in their phenotype, sub-types of breast cancer display various molecular lesions that participate in their pathogenesis. BRCA1 is one of the common hereditary cancer predisposition genes and encodes for an ubiquitin ligase. Ubiquitin ligases or E3 enzymes participate together with ubiquitin activating enzyme and ubiquitin conjugating enzymes in the attachment of ubiquitin (ubiquitination) in target proteins. Ubiquitination is a post-translational modification regulating multiple cell functions. It also plays important roles in carcinogenesis in general and in breast carcinogenesis in particular. Ubiquitin conjugating enzymes are a central component of the ubiquitination machinery and are often perturbed in breast cancer. This paper will discuss ubiquitin and ubiquitin-like proteins conjugating enzymes participating in breast cancer pathogenesis, their relationships with other proteins of the ubiquitination machinery and their role in phenotype of breast cancer sub-types.
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PMID:Ubiquitin- and ubiquitin-like proteins-conjugating enzymes (E2s) in breast cancer. 2318 32

The DNA repair function of the breast cancer susceptibility protein BRCA1 depends in part on its interaction with RAP80, which targets BRCA1 to DNA double-strand breaks (DSBs) through recognition of K63-linked polyubiquitin chains. The localization of BRCA1 to DSBs also requires sumoylation. We demonstrated that, in addition to having ubiquitin-interacting motifs, RAP80 also contains a SUMO-interacting motif (SIM) that is critical for recruitment to DSBs. In combination with the ubiquitin-binding activity of RAP80, this SIM enabled RAP80 to bind with nanomolar affinity to hybrid chains consisting of ubiquitin conjugated to SUMO. Furthermore, RNF4, a SUMO-targeted ubiquitin E3 ligase that synthesizes hybrid SUMO-ubiquitin chains, localized to DSBs and was critical for the recruitment of RAP80 and BRCA1 to sites of DNA damage. Our findings, therefore, connect ubiquitin- and SUMO-dependent DSB recognition, revealing that RNF4-synthesized hybrid SUMO-ubiquitin chains are recognized by RAP80 to promote BRCA1 recruitment and DNA repair.
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PMID:RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. 2321 28

The ubiquitin-proteasome pathway is a common cellular process in eukaryotic tissue. Ubiquitin binds to proteins and tags them for destruction; this tagging directs proteins to the proteosome in the cell that degrades and recycles unneeded proteins. The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins with respect to cell cycle control, transcription, apoptosis, cell adhesion, angiogenesis, and tumour growth. This review article discusses the various ways that the ubiquitin pathway is involved in ovarian cancer, such as modulating the ovarian-cancer-related gene BRCA1 and tumour suppressor p53, and interfering with the erk pathway, the cyclin-dependent cell cycle regulation process, and ERBB2 gene expression.
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PMID:Ubiquitin pathway and ovarian cancer. 2330 Mar 58


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