Abstract 4197: A DNA damage checkpoint response to unrepaired ultraviolet radiation-induced lesions which is defective in melanoma

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Ultraviolet radiation (UVR) is a major environmental risk factor in the development of skin cancer. Here we describe a G2 phase cell cycle checkpoint response to suberythemal doses of UVR that is defective in a majority of melanoma cell lines tested. The majority of cells in the basal layer of the epidermis are quiescent, and exposure to suberythemal doses of UVR produces not only DNA damage but also provides a mitogenic stimulus to drive cells into the cell cycle. The majority of UVR-induced DNA lesions are rapidly repaired by NER mechanisms, but a small number of DNA lesions fail to be repaired during G1 phase and are encountered by the replication fork during S phase. This triggers Werner helicase (Wrn) dependent lesion bypass, allowing replication to continue relatively unhindered, but producing gaps in the newly replicated DNA strand opposite the lesions. These single stranded DNA gaps recruit replication protein A (RPA) and components of the ATR-Chk1 checkpoint signaling responsible for the G2 phase arrest observed. The RPA foci also co-localise components of the error free RAD18-RAD51 post replication repair pathway which are essential for repair of the gaps and checkpoint signaling. This checkpoint mechanism ensures detection and repair of all UVR induced DNA damage before proceeding into mitosis. Loss of this checkpoint response increases the rate of UVR induced mutation. Thus this checkpoint response is critical for maintaining genomic stability in the epidermal melanocytes and keratinocytes, and loss of this checkpoint mechanism may account for the increased UVR signature DNA mutations found in melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4197. doi:10.1158/1538-7445.AM2011-4197