A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation.

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Citation

Esteve-Puig R, Gil R, Gonzalez-Sanchez E, Bech-Serra JJ, Grueso J, Hernandez-Losa J, Moline T, Canals F, Ferrer B, Cortes J, Bastian B, Ramon Y Cajal S, Martin-Caballero J, Flores JM, Vivancos A, Garcia-Patos V, Recio JA

A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation.

PLoS Genet. 2014 Oct 16;10(10):e1004721. doi: 10.1371/journal.pgen.1004721. eCollection 2014 Oct.

PubMed ID
25329316 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cyclin-dependent kinase inhibitor 1P38936Details
NUAK family SNF1-like kinase 1O60285Details