Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Mikhail Geyfman, Vivek Kumar, Qiang Liu, Rolando Ruiz, William Gordon, Francisco Espitia, Eric Cam, Sarah E. Millar, Padhraic Smyth, Alexander Ihler, Joseph S. Takahashi, Bogi Andersen

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day-dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times ofmaximum UV exposure, thus contributing to the high incidence of human skin cancers.

Original languageEnglish (US)
Pages (from-to)11758-11763
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number29
DOIs
StatePublished - Jul 17 2012

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Epidermis
DNA Damage
S Phase
Cell Proliferation
Muscles
Skin
Keratinocytes
Brain
Circadian Clocks
Proteins
Transcriptome
Genes
cdc Genes
Oxidative Phosphorylation
Skin Neoplasms
Cell Division
Hair
Reactive Oxygen Species
Incidence

Keywords

  • Arntl gene
  • Cell cycle
  • Circadian rhythm
  • UVB damage

ASJC Scopus subject areas

  • General

Cite this

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. / Geyfman, Mikhail; Kumar, Vivek; Liu, Qiang; Ruiz, Rolando; Gordon, William; Espitia, Francisco; Cam, Eric; Millar, Sarah E.; Smyth, Padhraic; Ihler, Alexander; Takahashi, Joseph S.; Andersen, Bogi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 29, 17.07.2012, p. 11758-11763.

Research output: Contribution to journalArticle

Geyfman, Mikhail ; Kumar, Vivek ; Liu, Qiang ; Ruiz, Rolando ; Gordon, William ; Espitia, Francisco ; Cam, Eric ; Millar, Sarah E. ; Smyth, Padhraic ; Ihler, Alexander ; Takahashi, Joseph S. ; Andersen, Bogi. / Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 29. pp. 11758-11763.
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AU - Millar, Sarah E.

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AB - The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day-dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times ofmaximum UV exposure, thus contributing to the high incidence of human skin cancers.

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