Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3

Moynihan, Terry P.; Ardley, Helen C.; Leek, J.P.; Thompson, John; Brindle, Nick; Markham, Alexander F.; Robinson, Philip A.

doi:10.1007/s003359900155

Cited by 22 publications

(20 citation statements)

References 41 publications

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“…UbcH7 was initially identified as the E2 enzyme that interacts with the E3 ligase, E6AP (26)(27)(28). UbcH7 can form a complex with BRCA1 in vitro, but failed to support the BRCA1-mediated Ub ligase activity (29).…”

Section: Resultsmentioning

confidence: 99%

UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted cells display increased nonhomologous end-joining and reduced homologous recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to DNA damage likely because they mainly used the errorprone nonhomologous end-joining pathway to repair DSBs. Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1.DNA damage response | UbcH7 | 53BP1 | protein degradation | DSB repair P rompt response to double-strand breaks (DSBs) caused by, for example, ionization radiation (IR), requires sequential and coordinated assembly of DNA damage response (DDR) proteins at damage sites (1). Recent research findings reveal key roles of the tumor suppressor p53-binding protein 1 (53BP1) and BRCA1 in the decision making of DSB repair. 53BP1, together with Rif1, suppress BRCA1-dependent homologous recombination (HR), thereby promoting nonhomologous end-joining (NHEJ) in G1 phase (2-6). Conversely, BRCA1 antagonizes 53BP1/Rif1, favoring HR in S and G2 phases (7,8). In the absence of BRCA1 or with enhanced retention of 53BP1 at DSB sites, cells primarily use the error-prone NHEJ to repair DSBs throughout the cell cycle, which leads to gene rearrangement, cell death, and increased sensitivity to anticancer therapies (9-11). Consistently, BRCA1-null mice are early embryonic lethal (12, 13) and codepletion of TP53BP1 rescued the lethality phenotype of BRCA1-null mice (12)(13)(14).Low expression level of 53BP1 was found to be associated with poor clinical outcome in triple negative breast cancer patients with BRCA1 mutation (12, 15), as well as resistance to genotoxins and poly(ADP-ribose) polymerase inhibitors (12,16,17). This finding is probably because loss of 53BP1 restored HR and promoted cell survival (12-14). Reduced expression of 53BP1 was also observed in tumors from the brain (18), lymph node (19), and pancreas (20). These data indicate that loss of 53BP1 might be a common mechanism for advanced tumors to evade from radiotherapy or chemotherapy. However, molecular mechanisms controlling the protein level of 53BP1 remain less well understood.Here we show that UbcH7, an E2 enzyme involved in the ubiquitin (Ub) pathway, controls the protein stability of 53BP1, thereby determining the DSB repair choice. Loss of UbcH7 sta...

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Section: Resultsmentioning

confidence: 99%

UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Direct sequencing of PAC DNA confirmed the presence of an intron between nucleotides 24-25 (Fig. 1A), a position corresponding to intron 1 of UBE2L3 (Moynihan et al, 1996(Moynihan et al, , 1998). Additional sequencing primers were then designed from the original cDNA sequence (Kumar et al, 1997), which would flank putative intron/exon junctions.…”

Section: Resultsmentioning

confidence: 99%

“…Due to their apparent functional redundancy, and similarities in primary amino acid structure, we sought to establish whether the genomic structure of UBE2L6 was similar at the DNA level to that of UBE2L3 (Moynihan et al, 1996(Moynihan et al, , 1998. This would imply that in addition to their apparent functional redundancy, the processing of these two genes may also have remained evolutionarily conserved.…”

Section: Ubch8mentioning

confidence: 99%

“…We have previously characterized the genomic structure of UBE2L3, the UbcH7 gene encoded by four exons (Moynihan et al, 1996(Moynihan et al, , 1998. Due to their apparent functional redundancy, and similarities in primary amino acid structure, we sought to establish whether the genomic structure of UBE2L6 was similar at the DNA level to that of UBE2L3 (Moynihan et al, 1996(Moynihan et al, , 1998.…”

Section: Ubch8mentioning

confidence: 99%

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Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12

Ardley¹,

Rose²,

Tan³

et al. 2000

Cytogenet Genome Res

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The human UBE2L6 gene encodes UbcH8^Kumar, a ubiquitin-conjugating enzyme (E2) highly simliar in primary structure to UbcH7 which is encoded by UBE2L3. Like UBC4 and UBC5 in yeast, these proteins demonstrate functional redundancy. Herein we report the intron/exon structure of UBE2L6. Comparison of the genomic organization of UBE2L6 with UBE2L3 demonstrates that these genes remain highly conserved at the genomic as well as at the protein level. We also describe the chromosomal localization of UBE2L6, which maps to chromosome 11q12.

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“…Studies in mice suggest that E2N, also known as "Ubc13," plays a role in DNA repair (52). The E2L3 enzyme participates in c-Fos degradation and NF-κB maturation in vitro and potentially could affect the pathways involved in cellular proliferation (53). We identified several genes classified in the Huntington's disease pathway, including Bax (BCL2-associated X protein), glutathione peroxidase 1 (Gpx1), and Huntingtin.…”

Section: Functional Classes Of Proteins and Pathways Changed By Exposmentioning

confidence: 99%

Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals

Williams

Lemieux

Hassis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Common environmental contaminants such as bisphenols and phthalates and persistent contaminants such as polychlorinated biphenyls are thought to influence tissue homeostasis and carcinogenesis by acting as disrupters of endocrine function. In this study we investigated the direct effects of exposure to bisphenol A (BPA), mono-n-butyl phthalate (Pht), and polychlorinated biphenyl 153 (PCB153) on the proteome of primary organotypic cultures of the mouse mammary gland. At low-nanomolar doses each of these agents induced distinct effects on the proteomes of these cultures. Although BPA treatment produced effects that were similar to those induced by estradiol, there were some notable differences, including a reduction in the abundance of retinoblastomaassociated protein and increases in the Rho GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle protein CDC42. Both Pht and PCB153 induced changes that were distinct from those induced by estrogen, including decreased levels of the transcriptional corepressor C-terminal binding protein 1. Interestingly, the three chemicals appeared to alter the abundance of distinct splice forms of many proteins as well as the abundance of several proteins that regulate RNA splicing. Our combined results indicate that the three classes of chemical have distinct effects on the proteome of normal mouse mammary cultures, some estrogen-like but most estrogen independent, that influence diverse biological processes including apoptosis, cell adhesion, and proliferation.proteomics | mammary epithelium | environmental chemicals | organotypic culture | estrogen B reast cancers are caricatures of normal tissue development (1-3). The same underlying mechanisms that affect the cell processes needed for normal mammary development contribute to cancer progression. By affecting the distribution of interacting cells and communication among them through nontargeted effects, carcinogens can promote the outgrowth of altered cells with malignant potential. Exposure to environmental agents can affect mammary gland development and alter breast cancer risk. Epidemiologic studies have associated a number of environmental factors with increased breast cancer risk (4). Some of these factors may have low-level effects that are not genotoxic but alter immune responses, vascularity, or the microenvironment or that change susceptibility to carcinogens. A current weakness in models of cancer risk assessment is the lack of consideration of factors that influence the susceptibility of mixed cell populations to transformation. Indeed, ionizing radiation, the prototypical carcinogen, promotes changes in the biochemical properties in cultured mouse and human breast cells, in the stromal environment, and in intact mouse mammary gland (5-7).Physiologically relevant 3D culture models can recapitulate crucial aspects of the dynamic and reciprocal signaling necessary for establishing and maintaining tissue-specific morphogenetic programs. The determination of the molecular mechanisms underlying m...

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Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3

Cited by 22 publications

References 41 publications

UbcH7 regulates 53BP1 stability and DSB repair

UbcH7 regulates 53BP1 stability and DSB repair

Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12

Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals

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