Does the interaction of Progerin and PCNA provoke genome instability and the activation of inflammatory pathways?

Progerin 和 PCNA 的相互作用是否会引起基因组不稳定和炎症通路的激活？

• 批准号: 9549377
• 负责人: Michael Seidman
• 金额: $ 9.45万
• 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/9549377
• 关键词: Adverse effects; Appearance; Binding; Cells; Complex; DNA; DNA Damage; DNA Interstrand Crosslinking; DNA Repair; DNA Repair Pathway; DNA-Directed DNA Polymerase; Data; Disease; Dominant-Negative Mutation; Enzymes; Fanconi Anemia pathway; Fanconi anemia protein; Fanconi' s Anemia; Genome; Genome Stability; Genomic Instability; Human; Inflammatory; Lamin Type A; Lamins; Link; Maintenance; Mediating; Monoubiquitination; Mutation; NF-kappa B; Nuclear Envelope; Pathway interactions; Point Mutation; Premature aging syndrome; Progeria; Proteins; RNA Splicing; Stress; Syndrome; Transact; Variant; age effect; env Gene Products; genome integrity; mutant; protein complex; repaired; response

PCNA is an essential co-factor for DNA polymerases in both replication and DNA repair. FANCM is a highly conserved DNA remodeling enzyme that promotes the activation of the Fanconi anemia DNA repair pathway and facilitates replication traverse of DNA interstrand crosslinks. We have shown that FANCM and PCNA are binding partners in the context of replication stress. The interaction is mediated through a conserved PIP-box in human FANCM, and this interaction is important for the cellular response to that stress. A FANCM variant carrying a mutation in the PIP-box is defective in promoting replication traverse of blocks to replication and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi Anemia pathway. We have also demonstrated a strong interaction between FANCM and the protein complex that drives replication, again in response to replication stress. Our data reveal a conserved interaction mode between FANCM and PCNA during replication stress, and suggest that this interaction is essential for FANCM to aid replication machines to traverse DNA blocks prior to post-replication repair.

PCNA是DNA聚合酶在复制和DNA修复中的重要辅助因子。FANCM是一种高度保守的DNA重塑酶，其促进范可尼贫血DNA修复途径的激活并促进DNA链间交联的复制遍历。我们已经表明，FANCM和PCNA的复制压力的背景下结合的合作伙伴。这种相互作用是通过人FANCM中保守的PIP盒介导的，并且这种相互作用对于细胞对该应激的反应是重要的。在PIP盒中携带突变的FANCM变体在促进复制跨越复制阻断方面有缺陷，并且在促进FANCD 2单泛素化（Fanconi贫血途径的关键步骤）方面也是无效的。我们还证明了FANCM和驱动复制的蛋白质复合物之间的强烈相互作用，再次响应复制应激。我们的数据揭示了一个保守的FANCM和PCNA之间的相互作用模式，在复制应力，并建议，这种相互作用是必不可少的FANCM，以帮助复制机遍历DNA块之前，复制后修复。