Multiple interaction nodes define the postreplication repair response to UV-induced DNA damage that is defective in melanomas and correlated with UV signature mutation load

Sandra Pavey, Alex Pinder, Winnie Fernando, Nicholas D’Arcy, Nicholas Matigian, Dubravka Skalamera, Kim Anh Lê Cao*, Dorothy Loo-Oey, Michelle M. Hill, Mitchell Stark, Michael Kimlin, Andrew Burgess, Nicole Cloonan, Richard A. Sturm, Brian Gabrielli*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)
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Abstract

Ultraviolet radiation-induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV-induced lesions, that is, the nucleotide excision repair pathway, appears intact in most melanomas. We have previously reported a postreplication repair mechanism that is commonly defective in melanoma cell lines. Here we have used a genome-wide approach to identify the components of this postreplication repair mechanism. We have used differential transcript polysome loading to identify transcripts that are associated with UV response, and then functionally assessed these to identify novel components of this repair and cell cycle checkpoint network. We have identified multiple interaction nodes, including global genomic nucleotide excision repair and homologous recombination repair, and previously unexpected MASTL pathway, as components of the response. Finally, we have used bioinformatics to assess the contribution of dysregulated expression of these pathways to the UV signature mutation load of a large melanoma cohort. We show that dysregulation of the pathway, especially the DNA damage repair components, are significant contributors to UV mutation load, and that dysregulation of the MASTL pathway appears to be a significant contributor to high UV signature mutation load.

Original languageEnglish
Pages (from-to)22-41
Number of pages20
JournalMolecular Oncology
Volume14
Issue number1
DOIs
Publication statusE-pub ahead of print - 6 Jan 2020
Externally publishedYes

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