Alternative Splicing of RAD6B and Not RAD6A is Selectively Increased in Melanoma: Identification and Functional Characterization
| Autor: | Seongho Kim, Carly E. Martin, Ambikai Gajan, Malathy P.V. Shekhar, Sandeep Mittal, Steven M. Firestine, Milap Joshi, Ido Sloma, Sharon K. Michelhaugh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
DNA Replication Male Skin Neoplasms DNA Repair Transcription Genetic Biology Article Cell Line whole exome sequencing Transcriptome 03 medical and health sciences alternative splicing 0302 clinical medicine Exome Sequencing medicine melanoma Humans histone ubiquitination Wnt Signaling Pathway Gene lcsh:QH301-705.5 beta Catenin Aged 030304 developmental biology Aged 80 and over 0303 health sciences Histone ubiquitination Melanoma Alternative splicing Wnt signaling pathway General Medicine Middle Aged medicine.disease Molecular biology Exon skipping 3. Good health lcsh:Biology (General) 030220 oncology & carcinogenesis Ubiquitin-Conjugating Enzymes Cutaneous melanoma Female exon skipping |
| Zdroj: | Cells, Vol 8, Iss 11, p 1375 (2019) Cells Volume 8 Issue 11 |
| ISSN: | 2073-4409 |
| Popis: | Rad6B, a principal component of the translesion synthesis pathway, and activator of canonical Wnt signaling, plays an essential role in cutaneous melanoma development and progression. As Rad6 is encoded by two genes, namely, UBE2A (RAD6A) and UBE2B (RAD6B), in humans, we compared their expressions in melanomas and normal melanocytes. While both genes are weakly expressed in normal melanocytes, Rad6B is more robustly expressed in melanoma lines and patient-derived metastatic melanomas than RAD6A. The characterization of RAD6B transcripts revealed coexpression of various splice variants representing truncated or modified functional versions of wild-type RAD6B in melanomas, but not in normal melanocytes. Notably, two RAD6B isoforms with intact catalytic domains, RAD6B&Delta exon4 and RAD6Bintron5ins, were identified. We confirmed that RAD6B&Delta exon4 and RAD6Bintron5ins variants are expressed as 14 and 15 kDa proteins, respectively, with functional in vivo ubiquitin conjugating activity. Whole exome sequence analysis of 30 patient-derived melanomas showed RAD6B variants coexpressed with wild-type RAD6B in all samples analyzed, and RAD6Bintron5ins variants were found in half the cases. These variants constitute the majority of the RAD6B transcriptome in contrast to RAD6A, which was predominantly wild-type. The expression of functional RAD6B variants only in melanomas reveals RAD6B&rsquo s molecular heterogeneity and its association with melanoma pathogenesis. |
| Databáze: | OpenAIRE |
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