Role of p53 homologs in DNA repair in human keratinocytes

p53 同源物在人类角质形成细胞 DNA 修复中的作用

• 批准号: 8195895
• 负责人: DENNIS H OH
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195895
• 关键词: Address; Affect; Award; Behavior; Burn injury; Cancer Etiology; Cell Line; Cells; Clinical; DNA Damage; DNA Repair; DNA lesion; DNA photoproducts; Development; Event; Family; Family member; Future; General Population; Genomics; Goals; Health; Healthcare; Heavy Metals; Homologous Gene; Human; In Vitro; Injury; Laboratories; Lead; Life; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Medical; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mutagenesis; Nucleotide Excision Repair; Oncogenes; Operative Surgical Procedures; Physiology; Population; Process; Protein Isoforms; Protein p53; Proteins; Publishing; Pyrimidine Dimers; Quality of life; Regulation; Resources; Risk; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Source; Squamous cell carcinoma; System; Testing; The Sun; Tissues; Trauma; Travel; Ultraviolet Rays; Undifferentiated; United States; Veterans; Work; Wound Healing; abstracting; base; body system; carcinogenesis; cell type; cost; keratinocyte; keratinocyte differentiation; killings; prevent; repaired; response; restoration; skin disorder; tumor; tumor progression; ultraviolet

Project Summary/Abstract Non-melanoma skin cancers are the most common malignancies in the general population of the United States and are highly prevalent in the veteran population. While not usually fatal, these skin cancers can be a major source of morbidity, impair quality of life, and utilize significant health care resources. Cumulative DNA damage in epidermal keratinocytes, particularly from solar ultraviolet radiation, is an important factor in the development of non-melanoma skin cancers. In addition, certain therapies for other skin diseases utilize DNA damaging agents that increase the risk of skin cancer. Bulky, distorting DNA lesions are removed by the process of nucleotide excision repair, but little is known about the regulation of DNA repair in keratinocytes. Clinical observations and recent in vitro studies, including those from the PI's laboratory, indicate that human keratinocytes possess unique mechanisms for regulating nucleotide excision repair. Loss of the tumor suppressor, p53, in non-keratinocyte cell types typically results in a loss of repair of the most abundant UVR- induced photoproduct. However, work during the current award period has documented that keratinocytes require loss of both p53 and another member of the family-p63-before repair is compromised. Furthermore, recent work in the PI's laboratory suggests that a dual deficiency in p53 and p63 is associated with impaired nucleotide excision repair in squamous cell carcinomas that could be exploited to preferentially kill these cancers. The current proposal seeks to understand the mechanisms by which p53 and p63 regulate DNA repair in human keratinocytes during normal physiology, and to determine their role in the genesis and behavior of non-melanoma skin cancers. We hypothesize that p53 and p63 coordinately regulate repair of the major UVR-induced DNA photoproducts in both undifferentiated and terminally differentiating keratinocytes, and that dysregulation of this process occurs in squamous cell carcinomas and provides a mechanism for mutagenesis and tumor progression that may be therapeutically exploitable. The hypotheses will be tested by the following Specific Aims: 1) To determine the mechanisms by which p53 and p63 regulate repair protein levels in keratinocytes; 2) To determine the role of p63 in nucleotide excision repair during keratinocyte differentiation; 3) To assess the response of nucleotide excision repair to p63 over-expression in keratinocytes; and 4) To model, characterize and correct p63-mediated repair dysregulation in squamous cell carcinomas. At its conclusion, this project will elucidate the molecular basis of the unique photoprotective mechanisms of epidermal skin cells, allow us to understand how these mechanisms are dysfunctional during skin carcinogenesis, and suggest new strategies for preventing and treating skin cancers.

项目总结/文摘