The fork protection complex promotes parental histone recycling and epigenetic memory

Area of Science:

• Epigenetics
• Molecular Biology
• Yeast Genetics

Background:

• Parental histone inheritance is crucial for maintaining epigenetic memory across cell divisions.
• The precise mechanisms ensuring equitable distribution of histones to daughter cells during DNA replication remain incompletely understood.

Purpose of the Study:

• To investigate the role of fission yeast Mrc1 (human CLASPIN) in coordinating parental histone inheritance during DNA replication.
• To elucidate the molecular mechanism by which Mrc1 ensures symmetric histone segregation and epigenetic transmission.

Main Methods:

• Utilized fission yeast genetics to create and analyze Mrc1 mutants.
• Employed AlphaFold for structural prediction of Mrc1-histone interactions.
• Performed biochemical and functional assays to validate predicted interactions and Mrc1 function.

Main Results:

• Mrc1 binds H3-H4 tetramers and acts as a central coordinator of histone inheritance.
• Mrc1 mutants exhibited disrupted parental histone segregation to the lagging strand, leading to loss of H3K9me-mediated gene silencing.
• AlphaFold and biochemical data revealed Mrc1 co-chaperones H3-H4 tetramers with Mcm2, with Mrc1 bridging histone and Mcm2 binding.
• Differentiated Mrc1 mutations demonstrated distinct roles in lagging-strand versus leading-strand histone recycling.

Conclusions:

• Mrc1 plays a dual role in histone recycling, essential for both lagging and leading strand DNA replication.
• Mrc1 functions as an intra-replisome co-chaperone, toggling histones between replication pathways to ensure epigenetic inheritance.
• This mechanism guarantees the faithful transmission of epigenetic information to both daughter cells.