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Wiley, Human Mutation: Variation, Informatics and Disease, 12(34), p. 1650-1661, 2013

DOI: 10.1002/humu.22433

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UBE 2 QL 1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumour suppressor gene, we characterised the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial renal cell carcinoma (RCC) and found that a previously uncharacterised gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was down-regulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3% respectively of sporadic RCC. Re-expression of UBE2QL1 in a deficient RCC cell line suppressed anchorage independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (a) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (b) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumour suppressor gene. This article is protected by copyright. All rights reserved.