Telomere dysfunction and genome instability in familial melanoma

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 DESCRIPTION (provided by applicant): Familial melanomas comprise 10% of all melanomas. A characteristic feature of melanomas is their strikingly complex genomic profiles, highlighted by genomic rearrangements and chromosome structural aberrations. However, mechanisms responsible for the chromosomal alterations that potentially drive tumorigenesis remain unclear. We postulate that melanomas with mutations disrupting the function of the Protection of Telomere 1 (POT1) protein depend upon the alternative, Lig4-independent NHEJ (A-NHEJ) pathway for DNA repair. We will use mouse models and human tumor samples to understand how progressive telomere dysfunction and activation of the A-NHEJ pathway generate pro-oncogenic chromosomal aberrations and the stepwise accumulation of mutational changes in favor of melanoma initiation and progression.