Role of homologous recombination in the replication stress response

项目概要/帕萨迪纳奖摘要 DNA的精确复制是维持基因组稳定性所必需的。复制分叉面临许多障碍， 导致叉子失速或断裂威胁完整性的内源性和外源性来源。双 链断裂修复途径，同源重组，在停滞复制叉中具有关键作用 独立于双链断裂。这一途径的重要性被遗传性乳腺癌患者强调， 染色体不稳定顺序和癌症易感综合征。虽然是一个密集的研究领域，如何 重组蛋白在复制叉处的功能知之甚少。全面了解 复制反应对于理解人类疾病的分子机制和 从而导致开发用于在复制应答基因中携带突变的患者的新疗法。的 PI的长期目标是阐明重组蛋白在复制应激反应中的作用。在 为了支持这一目标，PI和实验室已经建立了一个强大的中央功能分离等位基因， 重组酶，RAD 51，并揭示了重组辅助蛋白的新作用。的 这项工作的成功完成将使人们更好地理解重组蛋白所起的作用 以及如何保护基因组的完整性。

PROJECT SUMMARY/ABSTRACT FROM PARENT AWARD Precise replication of DNA is required to maintain genome stability. Replication forks face many obstacles from Endogenous and exogenous sources that result in fork stalling or breakage threatening integrity. The double strand break repair pathway, homologous recombination, has critical roles at stalled replication forks independent of double strand breaks. The importance of this pathway is highlighted by patients with inherited chromosomal instability orders and cancer predisposition syndromes. Although an intense area of study, how recombination proteins function at replication forks are poorly understood. A comprehensive understanding of the replication response is critical for the understanding the molecular mechanisms of human disease and to lead to development of novel therapeutics for patients harboring mutations in replication response genes. The long-term goal of the PI to elucidate the roles of recombination proteins in the replication stress response. In support of this goal, the PI and laboratory have established a powerful-separation-of-function allele of the central recombination enzyme, RAD51 and uncovered a novel role for a recombination accessory protein. The successful completion of this work will lead to a better of understanding of the role recombination proteins play at stalled replication forks and how protect the integrity of the genome.