UVA-induced upregulation of progerin suppresses 53BP1‑mediated NHEJ DSB repair in human keratinocytes via progerin-lamin A complex formation

Huang,Xin; Pan,Yun; Cao,Di; Fang,Sheng; Huang,Kun; Chen,Jin; Chen,Aijun

doi:10.3892/or.2017.5603

UVA-induced upregulation of progerin suppresses 53BP1‑mediated NHEJ DSB repair in human keratinocytes via progerin-lamin A complex formation

Authors:
- Xin Huang
- Yun Pan
- Di Cao
- Sheng Fang
- Kun Huang
- Jin Chen
- Aijun Chen
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Affiliations: Prescriptions Department, College of Traditional Chinese Medicine, Chongqing Medical University, Yuzhong, Chongqing, P.R. China, Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, P.R. China
Published online on: April 26, 2017 https://doi.org/10.3892/or.2017.5603
Pages: 3617-3624

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Abstract

Ultraviolet (UV) radiation is the primary risk factor underlying photoaging and photocarcinogenesis. Mounting research has focused on the role of DNA damage response pathways in UV-induced double-strand break (DSB) repair. In the present study, we hypothesized that UVA-induced aberrant progerin upregulation may adversely affect p53-binding protein 1 (53BP1)-mediated non-homologous end joining (NHE) DSB repair in human keratinocytes. Basal cell carcinoma (BCC) tumors and matching normal skin tissue were sampled (n=200) to investigate whether human keratinocytes display dysregulated progerin expression as a function of advancing age and BCC status. Newborn foreskin samples (n=9) were used as a source for primary keratinocyte cultures. We investigated the effects of UVA radiation on progerin and lamin A expression as well as the effects of the silencing of progerin on lamin A protein expression in UVA-irradiated keratinocytes. We investigated whether blocking progerin‑lamin A interaction was able to rescue UVA-induced lamin A protein downregulation, 53BP1 downregulation and 53BP1-mediated NHEJ DSB repair activity. Progerin upregulation in adult keratinocytes was associated with advancing age, not BCC status. In vitro, UVA exposure significantly upregulated progerin expression by favoring alternative LMNA gene transcript splicing. UVA exposure significantly downregulated free (unbound) lamin A protein levels via progerin-lamin A complex formation. UVA exposure significantly decreased 53BP1 protein levels via enhanced progerin-lamin A complex formation. UVA-induced progerin‑lamin A complex formation was largely responsible for suppressing 53BP1-mediated NHEJ DSB repair activity. The present study is the first to demonstrate that UVA-induced progerin upregulation adversely affects 53BP1-mediated NHEJ DSB repair in human keratinocytes via progerin‑lamin A complex formation.

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