Understanding and Targeting the R-Loop-Mediated DNA Damage Response at Telomeres

了解并靶向 R 环介导的端粒 DNA 损伤反应

• 批准号: 10716512
• 负责人: Li Lan
• 金额: $ 36.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716512
• 关键词: Aging; Bypass; Cell Aging; Cell division; Cells; Chemicals; Cockayne Syndrome; Critical Pathways; Cytoprotection; DNA Damage; DNA Repair Pathway; DNA biosynthesis; DNA lesion; DNA replication fork; Dependence; Future; Genomic Instability; Human; Investigation; Lesion; Link; Longevity; Malignant Neoplasms; Mediating; Molecular; Mus; Pathway interactions; Patients; Phenotype; Premature aging syndrome; Process; Proteins; RAD52 gene; Radiation; Reactive Oxygen Species; Role; Source; Stress; Telomerase; Telomere Pathway; Telomere Shortening; Testing; Untranslated RNA; anticancer research; cancer cell; cancer type; cell age; clinical investigation; coping; novel; oxidative DNA damage; oxidative damage; pre-clinical; protective pathway; repaired; response; senescence; sensor; targeted cancer therapy; telomere; telomere loss; tumorigenesis

Project Summary Oxidative DNA damage is frequently generated by radiation, chemicals, and endogenous oxygen radicals, contributing to genomic instability during both aging and tumorigenesis. Oxidative damage at telomeres can lead to telomere loss or attrition, which triggers cellular senescence and limits the lifespan of dividing cells. While it is clear that oxygen radicals can inflict multiple types of DNA lesions, how these lesions are repaired at telomeres is still largely unknown. By inducibly and locally generating reactive oxygen species (ROS) at telomeres, we discovered a novel DNA repair pathway critical for the protection of cells against telomeric oxidative damage. This pathway is activated by ROS-induced R-loops, and is mediated by break-induced replication (BIR), a process that “jumpstarts” DNA synthesis at collapsed replication forks. In parallel with our studies on the oxidative damage response at telomeres, we also investigated how cancer cells maintain telomeres to bypass senescence. In particular, we have molecularly dissected the alternative lengthening of telomere (ALT) pathway, which is used by ~10-15% of human cancers to extend telomeres. Interestingly, we found that ALT is also an R-loop-triggered and BIR-mediated repair pathway. The unexpected similarities between the repair pathway dealing with telomeric oxidative damage and the ALT pathway lead us to hypothesize that these telomere repair pathways are mechanistically linked. Furthermore, cancer cells hijack the R-loop and BIR-mediated repair pathway to extend telomeres and bypass senescence. In Aim 1, we will systematically delineate the R-loop and BIR-mediated pathway that repairs telomeric oxidative damage, and investigate if this pathway contributes to ALT activation in cancer cells. In Aim 2, we will develop strategies to exploit the cellular dependency on the R-loop and BIR-mediated ALT pathway, which may allow us to selectively kill ALT+ cancer cells and aged cells harboring high telomeric oxidative damage. Our studies may establish a new link between cellular aging and tumorigenesis, and provide new opportunities to eliminate cancer cells by targeting a hijacked DNA repair pathway. These studies may have transformative impacts at the interface between aging and cancer research, opening a new avenue to future preclinical and clinical investigations.

项目总结