Mrc1 facilitates epigenetic inheritance through proper parental histone segregation
Chromatin-based epigenetic memory relies on the equal distribution of parental histone tetramers, which serve as templates for duplicating parental chromatin, to newly synthesized daughter DNA strands. Histone chaperones within the replisome, such as the histone binding domains (HBDs) of Mcm2 and Pol alpha, are critical for transferring parental histones to the lagging strand. However, the mechanisms and impact of parental histone transfer on epigenetic inheritance remain debated. Using fission yeast heterochromatin assembly as a model, we discovered that replisome component Mrc1 is crucial for both epigenetic inheritance and transfer of parental histones to the lagging strand, akin to  a Mcm2-HBD mutation. Isolation of separation-of-function mutations revealed that Mrc1's role in epigenetic inheritance is distinct form its DNA replication checkpoint and replisome speed control functions. Instead, Mrc1 prevents undesirable replisome interactions to facilitate interactions between Mcm2 and Pol alpha for the proper passage of parental histones. These findings unveil a novel function of Mrc1 and underscore the critical role of parental histone segregation in epigenetic inheritance. Overall design: H3K4me3 eSPAN performed in S.pombe followed by Next Generation Sequencing