Brahma deficiency in keratinocytes promotes UV carcinogenesis by accelerating the escape from cell cycle arrest and the formation of DNA photolesions

Ultraviolet radiation (UVR) is the principal cause of keratinocyte skin cancers. Previous work found that levels of the chromatin remodelling protein, Brahma (Brm), are diminished during the progression from actinic keratoses to cutaneous squamous cell carcinomas in humans, and its loss in UV-irradi...

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Bibliographic Details
Published in:Journal of dermatological science 2018-12, Vol.92 (3), p.254-263
Main Authors: Farrell, Andrew W., Halliday, Gary M., Lyons, J. Guy
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis - genetics
Cell cycle arrest
Cell Cycle Checkpoints - genetics
Cell Cycle Checkpoints - radiation effects
Cell Line
Cutaneous squamous cell carcinoma
DNA damage
DNA Damage - radiation effects
Humans
Keratinocytes - metabolism
Keratinocytes - pathology
Mice
Mice, Knockout
MicroRNAs - metabolism
Primary Cell Culture
Pyrimidine Dimers - radiation effects
Skin - cytology
Skin - pathology
Skin Neoplasms - genetics
Skin Neoplasms - pathology
SWI/SNF
Transcription Factors - deficiency
Transcription Factors - genetics
Ultraviolet Rays - adverse effects
UV radiation
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Summary:Ultraviolet radiation (UVR) is the principal cause of keratinocyte skin cancers. Previous work found that levels of the chromatin remodelling protein, Brahma (Brm), are diminished during the progression from actinic keratoses to cutaneous squamous cell carcinomas in humans, and its loss in UV-irradiated mouse skin causes epidermal hyperplasia and increased tumour incidence. The skins of mice and mouse and human keratinocytes deficient in Brm were exposed to UVR and evaluated for cell cycle progression and DNA damage response. To identify the mechanisms by which loss of Brm contributes to UVR-induced skin carcinogenesis. In both mouse keratinocytes and HaCaT cells, Brm deficiency led to an increased cell population growth following UVR exposure compared to cells with normal levels of Brm. Cell cycle analysis using a novel assay showed that Brm-deficient keratinocytes entered cell cycle arrest normally, but escaped from cell cycle arrest faster, enabling them to begin proliferating earlier. In mouse keratinocytes, Brm primarily affected accumulation in G0/G1-phase, whereas in HaCaT cells, which lack normal p53, accumulation in G2/M-phase was affected. Brm-deficient keratinocytes in mouse skin and human cell cultures also had higher levels of UVR-induced cyclobutane pyrimidine dimer photolesions. These effects occurred without any compensatory increase in DNA repair or cell death to remove photolesions or the cells that harbor them from the keratinocyte population. The loss of Brm in keratinocytes exposed to UVR enables them to resume proliferation while harboring DNA photolesions, leading to an increased fixation of mutations and, consequently, increased carcinogenesis.
ISSN:0923-1811
1873-569X
DOI:10.1016/j.jdermsci.2018.11.006