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Abstract
Author SummaryLike all molecules in living organisms, DNA undergoes spontaneous decay and is constantly under attack by endogenous and environmental agents. Unlike other molecules, however, DNA—the blueprint of heredity—cannot be re-created de novo; it can only be copied. The original blueprint must therefore remain pristine. All kinds of DNA damage pose a health hazard. DNA lesions induced by the ultraviolet (UV) component of sunlight, for example, can lead to skin aging and skin cancer. A repair process known as nucleotide excision repair (NER) is dedicated to correcting this UV damage. Although the enzymatic steps of this repair process are known in detail, we still do not understand how it copes with the native situation in the cell, where the DNA is tightly wrapped around protein spools called nucleosomes. Our study has revealed the molecular mechanism by which an enigmatic component of NER called UV-DDB stimulates excision of UV-induced lesions in the landscape of nucleosome-packaged DNA in human skin cells. In particular, we describe how this accessory protein prioritizes, in space and time, which UV lesions in packaged DNA to target for repair by NER complexes, thus optimizing the repair process.
Highlights
Ultraviolet (UV) light generates mutagenic DNA lesions in the skin, primarily 6-4 pyrimidine-pyrimidone photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs) [1] whose cytotoxic, inflammatory, and carcinogenic effects are mitigated by nucleotide excision repair (NER)
A repair process known as nucleotide excision repair (NER) is dedicated to correcting this UV damage
Our study has revealed the molecular mechanism by which an enigmatic component of NER called UV-damaged DNA-binding (UV-DDB) stimulates excision of UV-induced lesions in the landscape of nucleosomepackaged DNA in human skin cells
Summary
Ultraviolet (UV) light generates mutagenic DNA lesions in the skin, primarily 6-4 pyrimidine-pyrimidone photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs) [1] whose cytotoxic, inflammatory, and carcinogenic effects are mitigated by nucleotide excision repair (NER). A widely accepted unproven model is that UV-DDB recognizes these lesions and delivers the substrate to XPC, which is the actual NER initiator [22,23,24,25,26] This putative handover remained elusive because it is not possible, for example in electrophoretic mobility shift assays, to detect stable intermediates where UVDDB and XPC bind to the same damage simultaneously [23,24,27]. The concomitant CUL4A-dependent ubiquitylation of XPC and histones is thought to potentiate the DNA-binding affinity of this repair initiator [25] and facilitate its access to chromatin [31,32], but such models have
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