A replisome-associated histone H3-H4 chaperone required for epigenetic inheritance

Area of Science:

• Epigenetics and Chromatin Biology
• Molecular Biology
• DNA Replication

Background:

• Inheritance of epigenetic information relies on the faithful transfer of parental histones to daughter DNA strands during replication.
• The precise mechanism by which intact histone H3-H4 tetramers are transported to the replication fork remains largely unknown.

Purpose of the Study:

• To identify key proteins involved in parental histone transfer during DNA replication.
• To elucidate the role of the replisome in coordinating histone distribution for epigenetic memory.

Main Methods:

• AlphaFold-Multimer structural predictions
• Biochemical assays
• Genetic approaches

Main Results:

• The Mrc1/CLASPIN subunit of the replisome was identified as a histone chaperone with a conserved histone-binding domain.
• Mrc1 binds H3-H4 tetramers, mimicking nucleosomal DNA and H2A-H2B histones, and is essential for heterochromatin inheritance and parental histone recycling.
• Binding sites for the FACT histone chaperone were found in Swi1/TIMELESS and DNA polymerase α, crucial for heterochromatin inheritance.

Conclusions:

• Mrc1 functions as a histone chaperone, crucial for distributing parental histones during replication.
• Mrc1, along with the FACT chaperone, coordinates the distribution of parental histones to ensure epigenetic state inheritance.