E2 Ligase dRad6 Regulates DMP53 Turnover in Drosophila

Su, Chunxia; Wei, Huimin; Lv, Wen; Wang, Da-Liang; Sun, Fang-Lin

doi:10.1074/jbc.m110.190314

Cited by 18 publications

(27 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous yeast two-hybrid screen identified multiple RAD6-interacting proteins, including p53, and we showed that RAD6 regulates the degradation of p53 in both Drosophila and mammalian cells (21,22). HP1␣, an important regulator of heterochromatin formation and transcriptional gene silencing, was also found to be one of the interacting partners of RAD6 in our yeast two-hybrid screen (data not shown).…”

Section: Resultsmentioning

confidence: 98%

“…In addition, several reports indicate that RAD6 regulates protein degradation by cooperating with different E3 ligases (17)(18)(19)(20). For instance, our previous studies have shown that the RAD6-MDM2 complex targets p53 for degradation both in Drosophila melanogaster and mammals (21,22). Additionally, a previous report indicated that in response to ionizing radiation (IR)-induced DNA DSBs, mammalian RAD6 forms a complex with RNF168 that is rapidly recruited to DSBs (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

RAD6 Promotes Homologous Recombination Repair by Activating the Autophagy-Mediated Degradation of Heterochromatin Protein HP1

Chen

Wang

Sun

et al. 2015

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

dEfficient DNA double-strand break (DSB) repair is critical for the maintenance of genome stability. Unrepaired or misrepaired DSBs cause chromosomal rearrangements that can result in severe consequences, such as tumorigenesis. RAD6 is an E2 ubiquitin-conjugating enzyme that plays a pivotal role in repairing UV-induced DNA damage. Here, we present evidence that RAD6 is also required for DNA DSB repair via homologous recombination (HR) by specifically regulating the degradation of heterochromatin protein 1␣ (HP1␣). Our study indicates that RAD6 physically interacts with HP1␣ and ubiquitinates HP1␣ at residue K154, thereby promoting HP1␣ degradation through the autophagy pathway and eventually leading to an open chromatin structure that facilitates efficient HR DSB repair. Furthermore, bioinformatics studies have indicated that the expression of RAD6 and HP1␣ exhibits an inverse relationship and correlates with the survival rate of patients. Double-strand breaks (DSBs) in DNA are considered the most deleterious types of DNA damage and pose a great threat to the integrity of the genome. Two pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ), have evolved in mammals to repair the broken ends that characterize DSBs (1). The HR pathway is a precise repair pathway, wherein missing and damaged sequence information is copied from sister chromatids to catalyze the repair (2, 3). In contrast, the repair of DNA DSBs by NHEJ is more error prone and often leads to insertions, deletions, or other types of chromosomal rearrangements. The accumulation of DNA mutations, due to either unrepaired broken ends or improper repair, is thought to increase the incidence rate of cancer and other types of diseases (4, 5).Mounting evidence indicates that the ubiquitination of DSB repair proteins plays an important role in regulating DSB repair in mammals (6-8). Ubiquitination is classified into two types, monoubiquitination and polyubiquitination, depending on the number of ubiquitin molecules that become posttranslationally attached to target proteins. Monoubiquitinated proteins have been shown to participate in nonproteolytic pathways such as receptor trafficking, signal transduction, gene transcription, and DNA repair, while the polyubiquitination of substrates often leads to protein degradation either through the 26S proteasome pathway or through the autophagy pathway (9-12).Ubiquitination is catalyzed by a series of enzymes that includes the ubiquitin activation enzyme (E1), the ubiquitin-conjugating enzyme (E2), and the ubiquitin ligase (E3) (13). RAD6 is an E2 ubiquitin-conjugating enzyme with a well-described role in stimulating the repair of UV-induced DNA damage (7,14). In budding yeast, RAD6 interacts with RAD18 to catalyze the monoubiquitination of proliferating cell nuclear antigen (PCNA) on lysine 164, thereby promoting the error-prone DNA damage repair pathway by recruiting low-fidelity polymerases. Interestingly, the interaction between the RAD6-RAD18 complex and the Ubc13-MMS2-Rad5 complex facilita...

show abstract

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

RAD6 Promotes Homologous Recombination Repair by Activating the Autophagy-Mediated Degradation of Heterochromatin Protein HP1

Chen

Wang

Sun

et al. 2015

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance, there is a lack of data examining the mechanism responsible for the overexpression of UBE2A in HCC tissue, or the substrate that UBE2A degrades in HCC progression. Previous studies have also indicated that UBE2A regulates p53 protein levels by transcriptional and post-transcriptional mechanisms in human cells (20,34). Thus, the mechanism of UBE2A involvement in the development of HCC should be clarified in the future.…”

Section: Discussionmentioning

confidence: 99%

High expression of ubiquitin-conjugating enzyme E2A predicts poor prognosis in hepatocellular carcinoma

Shen

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

Abstract. The present study aimed to illustrate the association of the expression of ubiquitin-conjugating enzyme E2A (UBE2A) with the clinicopathological parameters and prognosis in hepatocellular carcinoma (HCC). The expression levels of UBE2A mRNA and protein in a total of 276 HCC tissues and six liver cell lines was detected by fluorescent quantitative polymerase chain reaction, western blotting and immunohistochemistry. Statistical analysis was also performed to assess the association of the expression of UBE2A with the clinicopathological parameters and prognosis by the GraphPad Prism and SPSS version 21.0 software. UBE2A mRNA and protein were highly expressed in HCC tissues compared with those in the adjacent normal tissue. Immunohistochemical analysis revealed that UBE2A protein was more strongly stained in the 276 paraffin-embedded HCC tissues as compared with the 63 adjacent normal tissue. Statistical analysis also demonstrated that UBE2A expression was significantly associated with histological differentiation, TNM stage and vascular invasion of HCC (P<0.05). Notably, HCC patients with a high expression of UBE2A had a shorter survival time as compared with those with a low expression of UBE2A. There results suggested that UBE2A may be involved in the pathogenesis of HCC and may serve as an important prognostic marker.Further exploration of the involvement of UBE2A in HCC development may provide novel therapeutic targets. IntroductionHepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide and the fifth most common cancer type (1). HCC is a global health burden and its prevalence varies worldwide (2). The incidence rate is reported to be higher in Asia (>20 cases/100,000 individuals) in comparison with that in North America and Europe (<5 cases/100,000 individuals) (3). The prognosis of HCC is poor, as evident by the fact that the number of annual mortality cases (~600,000) is almost equal to the number of new cases diagnosed annually (4). The median rate for 1-year survival is 80% (range, 63-97%), for 3-year survival is 70% (range, 34-78%) and for 5-year survival is 50% (range, 17-69%) (5). Surgery remains the most important treatment strategy for patients with HCC. The 5-year survival rate of patients with early HCC subsequent to resection treatment reaches 50%, although these patients exhibit a high recurrence rate (6,7). Despite advances in the diagnosis (8) and treatment (9) of HCC, the prognosis of this disease remains poor (10). Therefore, further clarification of the mechanisms underlying its development is important (11,12).At present, the prognosis of HCC is predicted based on imaging findings and biomarkers. Various biomarkers, including α-fetoprotein (AFP) (13), des-γ-ca rboxy prothrombin (14) and α-l-fucosidase (15), have been identified over the past three decades. However, accurate indicators for the prognosis of HCC are limited. Consequently, there is an urgency to develop a novel biomarker for the prognosis of HCC.The ubiquitin system serves a ...

show abstract

“…In our recent studies, we found that Rad6 also targets the degradation of p53 in both Drosophila and mammals [6,7]. The molecular regulation of RAD6/BRE1 and H2BK120ub has been thoroughly investigated [5,8].…”

Section: Dear Editormentioning

confidence: 99%

“…The fact that RAD6 regulates both H2BK120ub and the degradation of p53 [6,7] raised the question of whether RAD6 also plays a role in stem cell differentiation. To test this possibility, we first performed western blot analysis to detect changes in the expression of RAD6 and several histone modifiers, including H2BK120ub.…”

Section: Dear Editormentioning

confidence: 99%

E2 Ligase dRad6 Regulates DMP53 Turnover in Drosophila

Cited by 18 publications

References 81 publications

RAD6 Promotes Homologous Recombination Repair by Activating the Autophagy-Mediated Degradation of Heterochromatin Protein HP1

RAD6 Promotes Homologous Recombination Repair by Activating the Autophagy-Mediated Degradation of Heterochromatin Protein HP1

High expression of ubiquitin-conjugating enzyme E2A predicts poor prognosis in hepatocellular carcinoma

Histone H2B lysine 120 monoubiquitination is required for embryonic stem cell differentiation

Contact Info

Product

Resources

About