RESEARCH:

I am currently interested in the circadian clock and the influence of the clock on DNA repair. The mammalian circadian clock consists principally of a transcription-translation feedback loop, in which the transcriptional activators BMAL and CLOCK bind to the promoters of clock-controlled genes as a heterodimer and drive transcription. The Cry and Per proteins are clock-controlled genes and repressors of BMAL-Clock. Thus Cry and Per repress their own expression. With delays in synthesis, nuclear entry and degradation, the net effect is a 24 hour rhythm in the expression of clock-controlled genes including the Cry and Per proteins. Studies have focused on the mechanism by which Cry and Per inhibit BMAL-Clock. To date, two mechanisms have been seen, one in which BMAL-Clock are removed from the promoter, and one in which Cry is stably bound to BMAL-Clock at the promoter.

The D. melanogaster clock functions in a largely analagous manner; however, in the fly, the Tim protein replaces Cry as an inhibitor of transcription. Cry is expressed as a flavoprotein which absorbs light. Absorption of light results in the Cry-mediated degradation of Tim protein. The consequence is the entrainment of transcriptional rhythmicity with the light-dark cycle. To date, the absorption of light has been shown to create a metastable conformational change in Cry, which results in altered protein-protein interactions, which lead to ubiquitination and degradation of Tim.

One of the subunits required for DNA excision repair of damage to DNA, the XPA protein, is expressed in a circadian manner. Consequently, DNA repair varies in efficiency according to the time of day. In the mouse, repair activity is low in the early morning, and it has been found that mice are more prone to skin cancer in the early morning. An association has also been seen between the low level of repair and higher sensitivity towards sunburn following early morning exposure to UV light as compared to exposure later in the day. Ongoing work is focused on the potential for chronotherapy based on circadian repair efficiency. Oxaliplatin is used in colorectal and other cancers and it is known to form DNA adducts. Nucleotide excision repair is the only system that repairs these adducts. The repair of the oxaliplatin adducts in neoplastic versus healthy tissues will be examined to find out if there is a basis for chronotherapy with this drug, and studies will also be conducted with mice bearing human colorectal explants to see if time-of-day treatment effects the response of the explants to drug.

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