Chromatin binding by HORMAD proteins regulates meiotic recombination initiation

Area of Science:

• Molecular Biology
• Genetics
• Structural Biology

Background:

• The meiotic chromosome axis is vital for chromosome organization, homologous recombination, and fertility.
• In yeast, the HORMAD protein Hop1 facilitates axis protein accumulation at nucleosome-rich sites via its central chromatin-binding region (CBR).

Purpose of the Study:

• To elucidate the structural mechanism by which the Hop1 CBR interacts with nucleosomal DNA.
• To investigate the functional consequences of disrupting the Hop1 CBR-nucleosome interaction on meiotic processes.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of Hop1 CBR bound to nucleosomal DNA.
• Genetic analysis of targeted Hop1 CBR mutants.
• Phylogenetic analysis of meiotic HORMAD proteins.

Main Results:

• Cryo-EM revealed that the Hop1 CBR recognizes bent nucleosomal DNA through a combined interface involving its PHD and winged helix-turn-helix domains.
• Disrupting the Hop1 CBR-nucleosome interface reduced axis protein binding and meiotic DNA double-strand breaks (DSBs) at axis islands, causing synapsis defects.
• Synthetic genetic interactions with Pch2 mutants suggest nucleosome binding regulates Hop1 conformation to control DSB formation.

Conclusions:

• The Hop1 CBR directly binds bent nucleosomal DNA, establishing a conserved mechanism for meiotic chromosome axis assembly.
• This interaction is critical for regulating meiotic DSB formation and ensuring proper chromosome synapsis and fertility.
• The ancient origin of the CBR indicates conserved roles for HORMAD proteins in meiosis across species.