A Mouse Model Uncovers LKB1 as an UVB-Induced DNA Damage Sensor Mediating CDKN1A (p21 ^WAF1/CIP1) Degradation

Abstract

Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.

Author Summary

Environmental insults are directly involved in cancer development. In particular, Ultraviolet (UV) radiation has been associated to the acquisition of different types skin cancer and premature skin aging. UV radiation causes modifications in the genetic material of cells (DNA) that if not repaired properly will lead to a mutated DNA (mutated genes) which might trigger the development of cancer. Understanding the molecular basis of the UV-induced DNA damage response is important to elucidate the mechanisms of skin homeostasis and tumorigenesis. Here we provide a UVB-induced skin cancer animal model showing that LKB1 tumor suppressor is also a DNA damage sensor. Importantly, the data suggest that reduced amounts of LKB1 protein in skin could be a risk factor for UV-induced skin carcinogenesis in humans.