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Claudia Benavente
Ph.D. Candidate
Cancer Biology GIDP
East Coast PARP Meeting 2006
Quebec, Canada
May 18 – 20, 2006
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“Cellular NAD Status as a Regulator of Skin Photodamage”
ABSTRACT
Our research is focused on the use of niacin, precursor of NAD, as an agent for early intervention in skin cancer. We hypothesize that the role of NAD as a substrate for PARPs, SIRTs and energy metabolism contribute significantly to human skin cells resistance to photo-damage. We have shown that subjects diagnosed with squamous cell carcinoma have lower NAD content in normal skin than individuals showing pre cancerous lesions. These findings raised the question as to whether niacin status in human skin modulates responses to photo-damage. Here, we provide experimental evidence that niacin and NAD modulate ROS formation, genomic stability, and resistance to light-induced damage. We have studied the consequences of solar simulated light or singlet oxygen (1O2)-induced photo-oxidative DNA damage in a human keratinocyte model with controlled niacin status. Our data show that keratinocytes with a sub-optimal NAD content have elevated ROS formation, increased autofluorescence, and reduced survival following exposure to solar simulated light or 1O2, relative to controls. More extensive restriction (2 weeks) results in increased NADP(H) pools, increased apoptotic rate, and inherent comet formation even in the absence of photo-oxidative stress. Our results support the hypothesis that NAD content is important in maintaining genomic integrity of skin cells. Currently, we are investigating the relative contributions of NAD acting through indirect mechanisms as a substrate for poly(ADP-ribose) polymerases (PARPs), sirtuins (SIRTs) and/or energy metabolism in photo-resistance. Supported in part by grants from NIH (CA43894, CA106677, PO1CA27502 and P30ES06694) and Niadyne, Inc.
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