Oral Presentation 6th Australian Health and Medical Research Congress 2012

Loss of Brm promotes the cell proliferative effects of ultraviolet radiation   (#190)

Nur mohammad monsur Hassan 1 , J. Guy Lyons 1 2 , Nicole Painter 1 , Nick Di Girolamo 3 , Gary M. Halliday 1
  1. Discipline of Dermatology, Bosch Institute, , Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  2. Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  3. School of Medical Sciences, , University of New South Wales, Sydney, Sydney, NSW, Australia

The mammalian chromatin remodelling complex SWI/SNF is known to modulate transcription and DNA repair in response to ultraviolet radiation (UV)-induced damage. The Brm subunit of the SWI/SNF complex is one of two mutually exclusive subunits that provide energy for remodelling and negatively regulates cell proliferation. Recently, we found that the absence of Brm increased skin and ocular photocarcinogenesis, suggesting Brm protects from some of the damaging effects of UVR. However, to date, the signaling pathways and mechanisms by which Brm protects from photocarcinogenesis are unknown. We hypothesised that loss of Brm promotes the proliferative effects of UV on keratinocytes. p53 mutations are an early event in squamous cell carcinogenesis. Therefore, we also investigated whether loss of p53 function interacted with Brm. C57BL/6 female mice with the following genotypes, p53+/+Brm+/+, p53+/+Brm-/-, p53+/-Brm+/+ and p53+/-Brm-/- were exposed to a bank of UVB and UVA emitting fluorescent tubes (250mJ/cm2 UVB and accompanying UVA to mimic solar UV) for 2-25 weeks. Non-irradiated age-matched mice provided control eyes and skin. Clinically normal skin and eyes were stained for proliferation and differentiation markers. Brm-/- mice had a more pronounced UV-induced epidermal hyperplasia at all time points compared to wild-type mice. After UV exposure (2 weeks and 25 weeks), Brm-/- epidermis also showed increased PCNA and Ki-67 expression indicating exacerbated UV-induced cellular proliferation. The cell cycle regulator E2F1 showed enhanced upregulation by UV in the Brm-/- epidermis compared to wild-type controls. Effects on cell proliferation were greater in mice with loss of a single p53 allele.  These experiments provide the first molecular evidence that when one allele of p53 is lost, Brm has additional tumor suppressing capability via dysregulation of cell cycle control in response to UV radiation.