Alternative Splicing of RAD6B and Not RAD6A is Selectively Increased in Melanoma: Identification and Functional Characterization

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dc.contributor.authorGajan, Ambikaien
dc.contributor.authorMartin, Carly E.en
dc.contributor.authorKim, Seonghoen
dc.contributor.authorJoshi, Milapen
dc.contributor.authorMichelhaugh, Sharon K.en
dc.contributor.authorSloma, Idoen
dc.contributor.authorMittal, Sandeepen
dc.contributor.authorFirestine , Stevenen
dc.contributor.authorShekhar, Malathy P. V.en
dc.date.accessioned2019-11-12T13:32:52Zen
dc.date.available2019-11-12T13:32:52Zen
dc.date.issued2019-11-01en
dc.date.updated2019-11-12T08:28:01Zen
dc.description.abstractRad6B, 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, <i>UBE2A</i> (<i>RAD</i><i>6A</i>) and <i>UBE2B</i> (<i>R</i><i>AD</i><i>6B</i>), 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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGajan, A.; Martin, C.E.; Kim, S.; Joshi, M.; Michelhaugh, S.K.; Sloma, I.; Mittal, S.; Firestine , S.; Shekhar, M.P.V. Alternative Splicing of RAD6B and Not RAD6A is Selectively Increased in Melanoma: Identification and Functional Characterization. Cells 2019, 8, 1375.en
dc.identifier.doihttps://doi.org/10.3390/cells8111375en
dc.identifier.urihttp://hdl.handle.net/10919/95496en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmelanomaen
dc.subjecthistone ubiquitinationen
dc.subjectalternative splicingen
dc.subjectexon skippingen
dc.subjectwhole exome sequencingen
dc.titleAlternative Splicing of RAD6B and Not RAD6A is Selectively Increased in Melanoma: Identification and Functional Characterizationen
dc.title.serialCellsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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