DNA polymerase ζ deficiency causes impaired wound healing and stress-induced skin pigmentation.

Sabine S Lange,Donna F Kusewitt,Sarita Bhetawal,Katherine Leslie Powell,Shelley Reh,Richard D Wood

doi:10.26508/lsa.201800048

Sabine S Lange, Donna F Kusewitt + Show 4 more

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https://doi.org/10.26508/lsa.201800048

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Abstract

DNA polymerase ζ (pol ζ) is a specialized enzyme important for DNA damage tolerance, facilitating synthesis past lesions caused by radiation or chemical damage. Here we report that disruption of Rev3l (encoding the catalytic subunit of pol ζ) in mouse epidermis leads to a defect in proliferation that impairs cutaneous wound healing. A striking increase in epidermal skin pigmentation accompanied both wound healing and UV irradiation in these mice. This was a consequence of stress-induced migration of Rev3l-proficient melanocytes to the Rev3l-defective epidermis. This pigmentation corresponded with p53 activation in keratinocytes and was absent in p53-negative areas of the epidermis. Expression of the kit ligand (Kitl) gene, a p53-controlled mediator of keratinocyte to melanocyte signaling, was enhanced during wound healing or following UV irradiation. This study extends the function of pol ζ to the process of proliferation during wound healing. Rev3l-deficient epidermis may be a useful mouse model system for examining communication between damaged keratinocytes and melanocytes, including signaling relevant to human disease.

Highlights

Many types of DNA damage are impediments to DNA replication [1]
We found that both wound healing and UV irradiation in adult mice engender striking epidermal skin pigmentation, caused by stress-induced migration of Rev3l-proficient melanocytes to the Rev3l-defective epidermis
Cre recombinase was driven by the bovine keratin-5 (BK5) promoter which is active in epithelia [17] but leaves Rev3l unaffected in the dermis (Fig 1C), melanocytes, and other non-epithelial tissues [14]

Summary

Introduction

One mode of DNA damage tolerance uses specialized DNA polymerases to bypass DNA damage [2]. The most critical of these specialized enzymes is DNA polymerase ζ (pol ζ ). Evidence is accumulating that pol ζ is frequently used in response to circumstances that stall DNA replication forks. Such circumstances include encounters with template DNA damage or with DNA sequences that interrupt replication, such as chromosomal fragile sites [3, 4] and stable non-B DNA structures [5, 6]. In the absence of Rev3l, which encodes the catalytic subunit of pol ζ , cells accumulate DNA double-strand breaks and chromosome aberrations [7, 8]. Inactivation of Rev3l results in embryonic lethality in mice [9, 10]

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