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

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Sep 25

PMID 30244834

Citations 109

Authors

Haiyun Gan

Albert Serra-Cardona

Xu Hua

Hui Zhou

Karim Labib

Chuanhe Yu

Zhiguo Zhang

Affiliations

Soon will be listed here.

Abstract

Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4) 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) 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) on leading strand, due to the impairment of the transfer of parental (H3-H4) 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) 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.

Citing Articles

Increased levels of lagging strand polymerase α in an adult stem cell lineage affect replication-coupled histone incorporation.

Davis B, Snedeker J, Ranjan R, Wooten M, Barton S, Blundon J Sci Adv. 2025; 11(9):eadu6799.

PMID: 40020063 PMC: 11870066. DOI: 10.1126/sciadv.adu6799.

Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability.

Kollenstart L, Biran A, Alcaraz N, Reveron-Gomez N, Solis-Mezarino V, Volker-Albert M Sci Adv. 2025; 11(8):eadr1453.

PMID: 39970210 PMC: 11837984. DOI: 10.1126/sciadv.adr1453.

A tale of two strands: Decoding chromatin replication through strand-specific sequencing.

Li Z, Zhang Z Mol Cell. 2025; 85(2):238-261.

PMID: 39824166 PMC: 11750172. DOI: 10.1016/j.molcel.2024.10.035.

H3K56 acetylation regulates chromatin maturation following DNA replication.

Duan S, Nodelman I, Zhou H, Tsukiyama T, Bowman G, Zhang Z Nat Commun. 2025; 16(1):134.

PMID: 39746969 PMC: 11697131. DOI: 10.1038/s41467-024-55144-7.

Molecular mechanism of parental H3/H4 recycling at a replication fork.

Nagae F, Murayama Y, Terakawa T Nat Commun. 2024; 15(1):9485.

PMID: 39488545 PMC: 11531469. DOI: 10.1038/s41467-024-53187-4.

References

Kurat C, Yeeles J, Patel H, Early A, Diffley J . Chromatin Controls DNA Replication Origin Selection, Lagging-Strand Synthesis, and Replication Fork Rates. Mol Cell. 2016; 65(1):117-130. PMC: 5222724. DOI: 10.1016/j.molcel.2016.11.016. View

Zhang Z, Shibahara K, Stillman B . PCNA connects DNA replication to epigenetic inheritance in yeast. Nature. 2000; 408(6809):221-5. DOI: 10.1038/35041601. View

Luger K, Mader A, Richmond R, Sargent D, Richmond T . Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 1997; 389(6648):251-60. DOI: 10.1038/38444. View

Brogaard K, Xi L, Wang J, Widom J . A map of nucleosome positions in yeast at base-pair resolution. Nature. 2012; 486(7404):496-501. PMC: 3786739. DOI: 10.1038/nature11142. View

Devbhandari S, Jiang J, Kumar C, Whitehouse I, Remus D . Chromatin Constrains the Initiation and Elongation of DNA Replication. Mol Cell. 2016; 65(1):131-141. PMC: 5256687. DOI: 10.1016/j.molcel.2016.10.035. View

Villa F, Simon A, Ortiz Bazan M, Kilkenny M, Wirthensohn D, Wightman M . Ctf4 Is a Hub in the Eukaryotic Replisome that Links Multiple CIP-Box Proteins to the CMG Helicase. Mol Cell. 2016; 63(3):385-96. PMC: 4980431. DOI: 10.1016/j.molcel.2016.06.009. View

Yu C, Gan H, Serra-Cardona A, Zhang L, Gan S, Sharma S . A mechanism for preventing asymmetric histone segregation onto replicating DNA strands. Science. 2018; 361(6409):1386-1389. PMC: 6597248. DOI: 10.1126/science.aat8849. View

Richet N, Liu D, Legrand P, Velours C, Corpet A, Gaubert A . Structural insight into how the human helicase subunit MCM2 may act as a histone chaperone together with ASF1 at the replication fork. Nucleic Acids Res. 2015; 43(3):1905-17. PMC: 4330383. DOI: 10.1093/nar/gkv021. View

Ransom M, Dennehey B, Tyler J . Chaperoning histones during DNA replication and repair. Cell. 2010; 140(2):183-95. PMC: 3433953. DOI: 10.1016/j.cell.2010.01.004. View

10.

Smith D, Whitehouse I . Intrinsic coupling of lagging-strand synthesis to chromatin assembly. Nature. 2012; 483(7390):434-8. PMC: 3490407. DOI: 10.1038/nature10895. View

11.

Yu C, Gan H, Zhang Z . Both DNA Polymerases δ and ε Contact Active and Stalled Replication Forks Differently. Mol Cell Biol. 2017; 37(21). PMC: 5640813. DOI: 10.1128/MCB.00190-17. View

12.

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

13.

Gan H, Yu C, Devbhandari S, Sharma S, Han J, Chabes A . Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress. Mol Cell. 2017; 68(2):446-455.e3. PMC: 5802358. DOI: 10.1016/j.molcel.2017.09.018. View

14.

Wal M, Pugh B . Genome-wide mapping of nucleosome positions in yeast using high-resolution MNase ChIP-Seq. Methods Enzymol. 2012; 513:233-50. PMC: 4871120. DOI: 10.1016/B978-0-12-391938-0.00010-0. View

15.

Janke R, King G, Kupiec M, Rine J . Pivotal roles of PCNA loading and unloading in heterochromatin function. Proc Natl Acad Sci U S A. 2018; 115(9):E2030-E2039. PMC: 5834728. DOI: 10.1073/pnas.1721573115. View

16.

Martin C, Zhang Y . Mechanisms of epigenetic inheritance. Curr Opin Cell Biol. 2007; 19(3):266-72. DOI: 10.1016/j.ceb.2007.04.002. View

17.

Simon A, Zhou J, Perera R, van Deursen F, Evrin C, Ivanova M . A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome. Nature. 2014; 510(7504):293-297. PMC: 4059944. DOI: 10.1038/nature13234. View

18.

Fu Y, Yardimci H, Long D, Ho T, Guainazzi A, Bermudez V . Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell. 2011; 146(6):931-41. PMC: 3209622. DOI: 10.1016/j.cell.2011.07.045. View

19.

Georgescu R, Yuan Z, Bai L, de Luna Almeida Santos R, Sun J, Zhang D . Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proc Natl Acad Sci U S A. 2017; 114(5):E697-E706. PMC: 5293012. DOI: 10.1073/pnas.1620500114. View

20.

Campos E, Stafford J, Reinberg D . Epigenetic inheritance: histone bookmarks across generations. Trends Cell Biol. 2014; 24(11):664-74. PMC: 4254315. DOI: 10.1016/j.tcb.2014.08.004. View