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

增殖细胞核抗原是DNA聚合酶在复制和DNA修复过程中必不可少的辅助因子。FANCM是一种高度保守的DNA重塑酶，它促进Fanconi贫血DNA修复途径的激活，并促进DNA链间交联的复制穿越。我们已经证明，在复制应激的背景下，FANCM和增殖细胞核抗原是结合伙伴。这种相互作用是通过人类FANCM中保守的PIP-box介导的，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变异体在促进复制穿过区块到复制方面存在缺陷，并且在促进FANCD2单素化方面也效率低下，FANCD2单素化是Fanconi贫血途径的关键步骤。我们还证明了FANCM和驱动复制的蛋白质复合体之间有很强的相互作用，这也是对复制压力的反应。我们的数据揭示了复制应激过程中FANCM和PCNA之间的一种保守的相互作用模式，并表明这种相互作用对于FANCM在复制后修复之前帮助复制机器遍历DNA块是必不可少的。

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.