Fanconi Anemia Pathway

范可尼贫血途径

• 批准号: 9351960
• 负责人: Robert Brosh
• 金额: $ 27.9万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9351960
• 关键词: BRCA1 gene; Binding; Biochemical Genetics; Biological Process; Chromosomal Instability; Clinical; DNA; DNA Damage; DNA Repair; DNA Structure; DNA replication fork; Data; Disease; Double Strand Break Repair; Fanconi Anemia pathway; Fanconi' s Anemia; Length; Link; Metabolism; Mismatch Repair; Molecular; Mutate; Mutation; Patients; Phenotype; Play; Proteins; Recombinants; Role; SS DNA BP; Stress; Substrate Specificity; Tail; Variant; Vertebral column; Work; base; crosslink; early onset; helicase; homologous recombination; insight; malignant breast neoplasm; novel; protein complex; repaired; response

Our recent work has focused on the roles of the FANCJ helicase in the DNA damage response. Mutations in the BRCA1-associated helicase BACH1 have been associated with early-onset breast cancer and cellular data suggest a role of the helicase in double strand break repair and checkpoint control. Recently, BACH1 (FANCJ) has been genetically linked to the chromosomal instability disorder Fanconi anemia (FA). To understand the molecular functions and biological substrates that FANCJ helicase acts upon, we have systematically evaluated the ability of purified recombinant FANCJ to unwind a panel of related DNA substrates with distinct tail variations including single-stranded versus double-stranded character, tail length, or backbone continuity. In addition, we have assessed the ability of BACH1 to catalytically unwind DNA structures proposed to be key intermediates of cellular DNA metabolism. The results from these unwinding studies provide a platform to investigate the molecular interactions of the FANCJ helicase with its protein partners in double strand break repair by homologous recombination. In terms of protein interactions, we have identified and characterized two novel FANCJ partners, the mismatch repair protein complex MutL alpha and the single-stranded DNA binding protein RPA. FANCJ interactions with these DNA repair factors play important roles in the DNA damage response. Our current efforts are directed toward understanding the roles of FANCJ in the classic FA pathway of cross-link repair as well as stabilization and progression of the replication fork.

我们最近的工作集中在FANCJ解旋酶在DNA损伤反应中的作用。 BRCA1相关的解旋酶BACH1中的突变与早发乳腺癌有关，细胞数据表明解旋酶在双链断裂修复和检查点控制中的作用。 最近，Bach1（FANCJ）与染色体不稳定性疾病芬科尼（Fanemia）（FA）有关。 为了了解FANCJ解旋酶作用的分子功能和生物底物，我们系统地评估了纯化的重组FANCJ放弃具有不同尾巴变化的相关DNA底物的能力，这些DNA底物具有不同的尾巴变化，包括单链和双链性角色，尾部长度，尾巴连续性或背链连续性。此外，我们已经评估了Bach1催化解脱DNA结构的能力，该结构被认为是细胞DNA代谢的关键中间体。这些放松研究的结果提供了一个平台，可以通过同源重组来研究FANCJ解旋酶与其蛋白质伴侣的分子相互作用。 在蛋白质相互作用方面，我们已经确定并表征了两个新型FANCJ伴侣，不匹配的修复蛋白复合物mutl alpha和单链DNA结合蛋白RPA。 FANCJ与这些DNA修复因子的相互作用在DNA损伤反应中起着重要作用。 我们目前的努力是为了理解FANCJ在经典的交联修复的经典FA途径以及复制叉的稳定和进展中的作用。