Abstract
Nucleotide excision repair (NER) is a major mechanism for removal of DNA lesions induced by exposure to UV radiation in the epidermis. Recognition of damaged DNA sites is the initial step in their repair, and requires multiprotein complexes that contain XPC and hHR23 proteins, or their orthologues. A variety of transcription factors are also involved in NER, including E2F1. In epidermal keratinocytes, UV exposure induces E2F1 phosphorylation, which allows it to recruit various NER factors to sites of DNA damage. However, the relationship between E2F1 and hHR23 proteins vis-à-vis NER has remained unexplored. We now show that E2F1 and hHR23 proteins can interact, and this interaction stabilizes E2F1, inhibiting its proteasomal degradation. Reciprocally, E2F1 regulates hHR23A subcellular localization, recruiting it to sites of DNA photodamage. As a result, E2F1 and hHR23A enhance DNA repair following exposure to UV radiation, contributing to genomic stability in the epidermis.
Highlights
Nonmelanoma skin carcinomas are the most frequent malignancies in humans, accounting for about 40% of all diagnosed cancers in North America [1]
The mammalian orthologues of yeast Rad23 (HR23) proteins play dual roles in DNA nucleotide excision repair (NER) and modulation of ubiquitin-mediated protein degradation [5]
Quantitative polymerase chain reaction analysis revealed the presence of transcripts encoding mHR23A and mHR23B in the epidermis and the dermis, at levels comparable to those found in a variety of other tissues (Figure 1A)
Summary
Nonmelanoma skin carcinomas are the most frequent malignancies in humans, accounting for about 40% of all diagnosed cancers in North America [1]. Alarming increases in their frequency in the last two decades, in young adults, are associated with increased exposure to UV radiation, which is the primary risk factor [2]. Increased risk of developing nonmelanoma skin carcinoma occurs in individuals affected by xeroderma pigmentosum, an autosomal recessive genetic disorder that arises from an impaired ability of epidermal cells to repair damaged DNA [3]. Complexes containing the DNA damage recognition factor XPC bound to hHR23A or hHR23B associate with
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