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April 6th, 2025
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Cleveland Clinic
cancer biology
biorxiv

XPC loss-of-function triggers melanomagenesis through CDKN2A downregulation

Chelakkot, V. S.Open in Google Scholar•Thomas, K.Open in Google Scholar•Romigh, T.Open in Google Scholar•Bernat, A.Open in Google Scholar•Samuel, R.Open in Google Scholar•Goli, N.Open in Google Scholar•Rambhia, P.Open in Google Scholar•Ravichandran, S.Open in Google Scholar•Wang, Q.-E.Open in Google Scholar•Cooper, K.Open in Google Scholaret al.

We identified a novel XPC variant, c.2420+5G>A (XPCvar), in siblings with multiple melanomas, inherited alongside c.779+1G>T, which results in an absent or disrupted protein. Despite this, they exhibited nucleotide excision repair (NER) deficits comparable to their unaffected parents, suggesting an NER-independent tumor suppressor function for XPC. XPC knockdown increased cell proliferation and tumorigenicity in vitro without affecting NER. Single-cell RNA sequencing revealed lower Cdkn2a in Xpcvar/var mouse melanocytes. Additionally, XPC knockdown downregulated CDKN2A in vitro. Furthermore, patient fibroblasts showed decreased p16INK4a, which was rescued by XPC overexpression. ChIP-PCR and luciferase assays confirmed XPC binding to the CDKN2A promoter, initiating transcription. Premature stop codon read-through, induced by gentamicin, restored XPC and p16INK4A in patient fibroblasts. These suggest that XPC regulates CDKN2A and that XPC loss might promote melanomagenesis by downregulating CDKN2A, independent of its NER function. Furthermore, we provide preclinical evidence for potential preventive and/or therapeutic strategies for similarly affected individuals.

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