The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands

Mol Cell. 2018 Oct 4;72(1):140-151.e3. doi: 10.1016/j.molcel.2018.09.001. Epub 2018 Sep 20.


Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polα axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)2 on leading strand, due to the impairment of the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Polα primase mutants that disrupt the connection of the CMG helicase to Polα that resides on lagging-strand template. Our results support a model whereby parental (H3-H4)2 complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polα complex to lagging-strand DNA for nucleosome assembly at the original location.

Keywords: Ctf4; DNA replication; Mcm2; Pol1; epigenetic inheritance; histone modifications; nucleosome assembly; parental histone transfer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin Assembly and Disassembly / genetics
  • DNA Helicases / genetics
  • DNA Polymerase III / genetics*
  • DNA Replication / genetics*
  • DNA-Binding Proteins / genetics*
  • Epigenesis, Genetic
  • Histones / genetics
  • Multiprotein Complexes / genetics
  • Nucleosomes / genetics
  • Protein Binding
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics*


  • CTF4 protein, S cerevisiae
  • DNA-Binding Proteins
  • Histones
  • Multiprotein Complexes
  • Nucleosomes
  • Saccharomyces cerevisiae Proteins
  • DNA polymerase A
  • DNA Polymerase III
  • DNA Helicases
  • MCM2 protein, S cerevisiae