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dc.contributor.advisorZaidi, M. Raza
dc.creatorAlp, Sarah
dc.date.accessioned2021-08-23T17:43:26Z
dc.date.available2021-08-23T17:43:26Z
dc.date.issued2021
dc.identifier.urihttp://hdl.handle.net/20.500.12613/6818
dc.description.abstractCutaneous malignant melanoma is the deadliest form of skin cancer with a rising incidence rate. Epidemiological studies show exposure to ultraviolet radiation (UVR) cause 80% of melanomas. However, the underlying molecular mechanisms by which UVR promotes melanomagenesis are unclear. The mutagenic properties of UVR are incontrovertible; however, well-studied driver mutations of melanomagenesis (BRAF V600E and NRAS Q61L/R) do not bear UVR signature mutations and so the role UVR mutations play in the early initiation of melanoma remains controversial. This highlights the gap in knowledge of the initial critical molecular mechanisms of UVR-induced melanomas and warrant investigating non-mutational mechanisms as causal factors of UVR-induced melanomagenesis. Aberrant DNA methylation is a signature of melanoma and regulates expression of important tumor suppressors. While epigenetic dysregulation is an important aspect of melanoma etiology, it has never been investigated in the context of UVR. We hypothesize that these initial UVR-induced DNA methylation changes may sensitize a field of melanocytes to acquiring subsequent complementary spontaneous and/or UVR-induced genetic mutations and render them susceptible to melanomagenesis. My preliminary data demonstrate that UVR can modulate DNA methylation in melanocytes and suggests a pigment dependent mechanism. UVR-induced DNA methylation changes in highly pigmented melanocytes primarily in intergenic regions as areas of active transcription were protected from 5’mC changes. Additionally, UVR induced long-term transcriptional changes in both dark and light pigmented melanocytes suggesting multiple epigenetic mechanisms being altered. Evaluation of the protein regulation of the enzymes involved in writing or erasing 5’mC point towards a dysregulation in TET2. Further work is needed to determine if changes in TET2 could contribute to the observed methylation changes. To determine if these methylation changes had any significance to melanoma development, they were compared to the skin cutaneous melanoma cohort in the TCGA database which found a modest correlation in UVR-induced methylation changes and those found in melanoma patients. Interestingly, 5’mC at UVR-sensitive sites was prognostic of patient survival. A highly pigmented human melanoma cell line was UV-irradiated to see if DNA methylation can also be affected in transformed cells; however, no changes were observed. This suggests UV-induced methylation contributes to early changes in melanoma development and/or other relevant physiological changes within the melanocytes. Altogether, these data identify a novel non-mutation mechanism by which UVR may contribute of melanomagenesis.
dc.format.extent144 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectMolecular biology
dc.subjectBiology
dc.subjectCellular biology
dc.subjectDNA methylation
dc.subjectEpigenetics
dc.subjectMelanocytes
dc.subjectMelanoma
dc.subjectUVR
dc.titleUVR Induces DNA Methylation Changes in Melanocytes
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberTempera, Italo
dc.contributor.committeememberSapienza, Carmen
dc.contributor.committeememberEngel, Nora
dc.contributor.committeememberIssa, Jean-Pierre
dc.contributor.committeememberSawaya, Bassel E.
dc.description.departmentCancer Biology & Genetics
dc.relation.doihttp://dx.doi.org/10.34944/dspace/6800
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
dc.identifier.proqst14545
dc.date.updated2021-08-21T10:06:40Z
refterms.dateFOA2021-08-23T17:43:27Z
dc.identifier.filenameAlp_temple_0225E_14545.pdf


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