Cutaneous melanocytes provide the major physiologic defense against the DNA damaging effects of ultraviolet (UV) radiation by synthesizing and distributing melanin to surrounding cells. Exposure to UV radiation is highly correlated with the transformation of normal melanocytes into melanoma. The mechanisms regulating the response to UV radiation and the steps leading to the oncogenic state have not been elucidated. A hallmark of exposure to UV radiation is an increase in pigmentation by enhanced transcription of genes required for melanin synthesis. Cells also respond to UV radiation by activation of pathways leading to cell cycle arrest, DNA repair, and apoptosis. To understand how a melanocyte responds to UV radiation, it is necessary to characterize the molecular mechanism involved. Activation of gene expression often involves alterations in chromatin structure to make it more accessible to the transcriptional machinery. SWI/SNF enzymes are multisubunit complexes that utilize the hydrolysis of ATP to remodel chromatin structure and facilitate transcription factor binding. They act as tumor suppressors, and are involved in gene regulation and cell cycle control. Preliminary evidence suggests that SWI/SNF enzymes are required for the activation of melanocyte specific genes (tyrosinase, trp1, and trp2) and for genes regulating cell cycle arrest (p21) and apoptosis (Bcl2). This proposal seeks to investigate the role that SWI/SNF enzymes play in the response to UV radiation.
Specific Aim 1 will determine whether SWI/SNF enzymes are required for the enhanced expression of tyrosinase, trp1, and trp2 and for the modulation of other genes upon exposure to UV radiation.
Specific Aim 2 will identify the mechanisms by which UV radiation results in activation of a melanocyte specific gene tyrosinase, by looking at changes in chromatin structure and transcription factor binding.
Specific Aim 3 will determine a role for SWI/SNF enzymes in cell cycle control.
