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

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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.