A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

Area of Science:

• Molecular Biology
• Epigenetics
• Structural Biology

Background:

• Chromatin assembly involves recycling old histones and depositing new ones during DNA replication.
• The precise mechanisms integrating histone dynamics with DNA replication for genome and epigenome maintenance are not fully understood.

Purpose of the Study:

• To elucidate the role of human MCM2 in chaperoning histones H3-H4 during DNA replication.
• To understand how MCM2's histone-binding properties contribute to genome-wide histone recycling.

Main Methods:

• X-ray crystallography to determine the structures of MCM2 bound to histones H3-H4.
• Mutational analyses to assess the functional importance of MCM2's histone-binding domains (HBDs).

Main Results:

• Structural studies revealed MCM2's histone-binding domains interacting with H3-H4 tetramers and dimers, distinct from nucleosomal DNA binding sites.
• Mutations in the MCM2 HBD impaired its histone-chaperone function and cell proliferation.
• MCM2 was shown to chaperone canonical H3-H4, as well as H3.3 and CENPA histone variants.

Conclusions:

• MCM2 possesses a unique histone-binding mode that enables the replicative helicase to chaperone histones H3-H4.
• This MCM2 function is essential for normal cell proliferation and efficient genome-wide histone recycling during DNA replication.