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Yan Qing Gong, Ding Peng, Xiang Hui Ning, Xin Yu Yang, Xue Song Li, Li Qun Zhou, Ying Lu Guo
Ubiquitin-conjugating enzyme E2T (UBE2T), a member of the ubiquitin-conjugating E2 family in the ubiquitin-proteasome pathway, has been reported to be overexpressed in certain tumor types and to have an important role in the Fanconi anemia pathway. In the present study, the expression of UBE2T and its association with bladder cancer were investigated; to the best of our knowledge, this has not been reported previously. Immunohistochemistry and western blot analysis demonstrated that UBE2T was significantly upregulated in bladder cancer tissues and cell lines compared with adjacent normal bladder tissues and a normal human urinary tract epithelial cell line, respectively...
December 2016: Oncology Letters
Nicholas E Mamrak, Akiko Shimamura, Niall G Howlett
Fanconi anemia (FA) is a rare autosomal and X-linked genetic disease characterized by congenital abnormalities, progressive bone marrow failure (BMF), and increased cancer risk during early adulthood. The median lifespan for FA patients is approximately 33years. The proteins encoded by the FA genes function together in the FA-BRCA pathway to repair DNA damage and to maintain genome stability. Within the past two years, five new FA genes have been identified-RAD51/FANCR, BRCA1/FANCS, UBE2T/FANCT, XRCC2/FANCU, and REV7/FANCV-bringing the total number of disease-causing genes to 21...
October 13, 2016: Blood Reviews
Arno F Alpi, Viduth Chaugule, Helen Walden
Ubiquitin signalling is a fundamental eukaryotic regulatory system, controlling diverse cellular functions. A cascade of E1, E2, and E3 enzymes is required for assembly of distinct signals, whereas an array of deubiquitinases and ubiquitin-binding modules edit, remove, and translate the signals. In the centre of this cascade sits the E2-conjugating enzyme, relaying activated ubiquitin from the E1 activating enzyme to the substrate, usually via an E3 ubiquitin ligase. Many disease states are associated with dysfunction of ubiquitin signalling, with the E3s being a particular focus...
October 15, 2016: Biochemical Journal
Yu Wang, Hui Leng, Hui Chen, Lei Wang, Nan Jiang, Xin Huo, Bin Yu
Ubiquitin-conjugating enzyme E2T (UBE2T), a member of the E2 family, was found to be overexpressed in a great many cancers such as bladder cancer, lung cancer, and prostate cancer. However, there have been no reports on the role of UBE2T in osteosarcoma. In this study, we tried to make the effects of UBE2T on osteosarcoma clear. The study results showed that UBE2T was overexpressed in osteosarcoma tissues and cell lines. Moreover, UBE2T knockdown inhibited osteosarcoma cell proliferation, migration, and invasion...
2016: Oncology Research
Edward C Stanley, Paul A Azzinaro, David A Vierra, Niall G Howlett, Steven Q Irvine
Fanconi anemia (FA) is a human genetic disease characterized by congenital defects, bone marrow failure, and increased cancer risk. FA is associated with mutation in one of 24 genes. The protein products of these genes function cooperatively in the FA pathway to orchestrate the repair of DNA interstrand cross-links. Few model organisms exist for the study of FA. Seeking a model organism with a simpler version of the FA pathway, we searched the genome of the simple chordate Ciona intestinalis for homologs of the human FA-associated proteins...
2016: Evolutionary Bioinformatics Online
Hao Yu, Pei Xiang, Qi Pan, Yijiao Huang, Nanlan Xie, Weimin Zhu
Ubiquitin-conjugating enzyme E2T (UBE2T) is a member of the E2 family that mediates the ubiquitin-proteasome system and regulates gene expression. It is a major oncogene in several cancers such as lung cancer and breast cancer, while the potential functions of UBE2T in gastric cancer (GC) remains largely unknown. Here, we identified the roles of UBE2T in GC progression and its potential to act as a prognostic marker of GC. Our data demonstrated that UBE2T was significantly upregulated in gastric cancer tissues, and the high expression of UBE2T was significantly correlated with poor differentiation, high T classification, and poor prognosis...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Wei Hu, Lushan Xiao, Chuanhui Cao, Shengni Hua, Dehua Wu
Increasing evidence has shown that UBE2T plays an important role in genomic integrity and carcinogenesis; however, its role in nasopharyngeal carcinoma (NPC) has not been investigated. Here, we evaluated the clinicopathological significance of UBE2T in NPC and its underlying mechanisms. Using immunohistochemical analysis of UBE2T expression in NPC samples, we demonstrated that UBE2T is highly expressed in NPC tissues, which correlated with the T/M classification, skull invasion, and poor prognosis. The in vitro assay showed that UBE2T overexpression promoted proliferation, migration, and invasion of NPC cells, while UBE2T knockdown inhibited these processes...
March 22, 2016: Oncotarget
Mingxin Wen, Yongwon Kwon, Yongsheng Wang, Jian-Hua Mao, Guangwei Wei
Increased expression of ubiquitin-conjugating enzyme E2T (UBE2T) is reported in human prostate cancer. However, whether UBE2T plays any functional role in prostate cancer development remains unknown. We here report the first functional characterization of UBE2T in prostate carcinogenesis. Prostate cancer tissue array analysis confirmed upregulation of UBE2T in prostate cancer, especially these with distant metastasis. Moreover, higher level of UBE2T expression is associated with poorer prognosis of prostate cancer patients...
September 22, 2015: Oncotarget
Jennifer A Miles, Mark G Frost, Eilis Carroll, Michelle L Rowe, Mark J Howard, Ateesh Sidhu, Viduth K Chaugule, Arno F Alpi, Helen Walden
The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown...
August 21, 2015: Journal of Biological Chemistry
Kimberly A Rickman, Francis P Lach, Avinash Abhyankar, Frank X Donovan, Erica M Sanborn, Jennifer A Kennedy, Carrie Sougnez, Stacey B Gabriel, Olivier Elemento, Settara C Chandrasekharappa, Detlev Schindler, Arleen D Auerbach, Agata Smogorzewska
Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI...
July 7, 2015: Cell Reports
Elizabeth L Virts, Anna Jankowska, Craig Mackay, Marcel F Glaas, Constanze Wiek, Stephanie L Kelich, Nadine Lottmann, Felicia M Kennedy, Christophe Marchal, Erik Lehnert, Rüdiger E Scharf, Carlo Dufour, Marina Lanciotti, Piero Farruggia, Alessandra Santoro, Süreyya Savasan, Kathrin Scheckenbach, Jörg Schipper, Martin Wagenmann, Todd Lewis, Michael Leffak, Janice L Farlow, Tatiana M Foroud, Ellen Honisch, Dieter Niederacher, Sujata C Chakraborty, Gail H Vance, Dmitry Pruss, Kirsten M Timms, Jerry S Lanchbury, Arno F Alpi, Helmut Hanenberg
Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T...
September 15, 2015: Human Molecular Genetics
Asuka Hira, Kenichi Yoshida, Koichi Sato, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Akira Shimamoto, Hidetoshi Tahara, Etsuro Ito, Seiji Kojima, Hitoshi Kurumizaka, Seishi Ogawa, Minoru Takata, Hiromasa Yabe, Miharu Yabe
Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, increased cancer susceptibility, progressive bone marrow failure (BMF), and various developmental abnormalities resulting from the defective FA pathway. FA is caused by mutations in genes that mediate repair processes of interstrand crosslinks and/or DNA adducts generated by endogenous aldehydes. The UBE2T E2 ubiquitin conjugating enzyme acts in FANCD2/FANCI monoubiquitination, a critical event in the pathway. Here we identified two unrelated FA-affected individuals, each harboring biallelic mutations in UBE2T...
June 4, 2015: American Journal of Human Genetics
Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, Aye Su Hlaing, Gary M Kupfer, Patrick Sung
FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined...
May 2014: Nucleic Acids Research
Charlotte Hodson, Andrew Purkiss, Jennifer Anne Miles, Helen Walden
The combination of an E2 ubiquitin-conjugating enzyme with an E3 ubiquitin-ligase is essential for ubiquitin modification of a substrate. Moreover, the pairing dictates both the substrate choice and the modification type. The molecular details of generic E3-E2 interactions are well established. Nevertheless, the determinants of selective, specific E3-E2 recognition are not understood. There are ∼40 E2s and ∼600 E3s giving rise to a possible ∼24,000 E3-E2 pairs. Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex, revealing a specific and extensive network of additional electrostatic and hydrophobic interactions...
February 4, 2014: Structure
Dilek Colak, Asmaa Nofal, Albandary Albakheet, Maimoona Nirmal, Hatim Jeprel, Abdelmoneim Eldali, Taher Al-Tweigeri, Asma Tulbah, Dahish Ajarim, Osama Al Malik, Mehmet S Inan, Namik Kaya, Ben H Park, Suad M Bin Amer
Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies...
2013: PloS One
Ian R Kelsall, Judith Langenick, Craig MacKay, Ketan J Patel, Arno F Alpi
The many proteins that function in the Fanconi anaemia (FA) monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes--UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity...
2012: PloS One
Koichi Sato, Kazue Toda, Masamichi Ishiai, Minoru Takata, Hitoshi Kurumizaka
FANCI and FANCD2 form a complex, and play essential roles in the repair of interstrand DNA crosslinks (ICLs) by the Fanconi anemia (FA) pathway. FANCD2 is monoubiquitylated by the FA core complex, composed of 10 FA proteins including FANCL as the catalytic E3 subunit. FANCD2 monoubiquitylation can be reconstituted with purified minimal components, such as FANCI, E1, UBE2T (E2) and FANCL (E3) in vitro; however, its efficiency is quite low as compared to the in vivo monoubiquitylation of FANCD2. In this study, we found that various forms of DNA, such as single-stranded, double-stranded and branched DNA, robustly stimulated the FANCD2 monoubiquitylation in vitro up to a level comparable to its in vivo monoubiquitylation...
May 2012: Nucleic Acids Research
Charlotte Hodson, Ambrose R Cole, Laurence P C Lewis, Jennifer A Miles, Andrew Purkiss, Helen Walden
The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links. At the heart of this pathway is the monoubiquitination of the FANCI-FANCD2 (ID) complex by the multiprotein "core complex" containing the E3 ubiquitin ligase FANCL. Vertebrate organisms have the eight-protein core complex, whereas invertebrates apparently do not. We report here the structure of the central domain of human FANCL in comparison with the recently solved Drosophila melanogaster FANCL. Our data represent the first structural detail into the catalytic core of the human system and reveal that the central fold of FANCL is conserved between species...
September 16, 2011: Journal of Biological Chemistry
Chantal H M A Ramaekers, Twan van den Beucken, Alice Meng, Shaqil Kassam, John Thoms, Robert G Bristow, Bradly G Wouters
BACKGROUND AND PURPOSE: Hypoxia is a common feature of the microenvironment of solid tumors which has been shown to promote malignancy and poor patient outcome through multiple mechanisms. The association of hypoxia with more aggressive disease may be due in part to recently identified links between hypoxia and genetic instability. For example, hypoxia has been demonstrated to impede DNA repair by down-regulating the homologous recombination protein RAD51. Here we investigated hypoxic regulation of UBE2T, a ubiquitin ligase required in the Fanconi anemia (FA) DNA repair pathway...
October 2011: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Yingying Zhang, Xiaowei Zhou, Lixia Zhao, Chao Li, Hengqi Zhu, Long Xu, Liran Shan, Xiang Liao, Zekun Guo, Peitang Huang
Fanconi anemia (FA) is a rare cancer-predisposing genetic disease mostly caused by improper regulation of the monoubiquitination of Fanconi anemia complementation group D2 (FANCD2). Genetic studies have indicated that ubiquitin conjugating enzyme UBE2T and HHR6 could regulate FANCD2 monoubiquitination through distinct mechanisms. However, the exact regulation mechanisms of FANCD2 monoubiquitination in response to different DNA damages remain unclear. Here we report that UBE2W, a new ubiquitin conjugating enzyme, could regulate FANCD2 monoubiquitination by mechanisms different from UBE2T or HHR6...
February 2011: Molecules and Cells
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