The Cell-cycle Choreography of H3 Variants Shapes the Genome

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Sep 21

PMID 37734377

Authors

Kamila Delaney

Nicole Weiss

Genevieve Almouzni

Affiliations

Soon will be listed here.

Abstract

Histone variants provide versatility in the basic unit of chromatin, helping to define dynamic landscapes and cell fates. Maintaining genome integrity is paramount for the cell, and it is intimately linked with chromatin dynamics, assembly, and disassembly during DNA transactions such as replication, repair, recombination, and transcription. In this review, we focus on the family of H3 variants and their dynamics in space and time during the cell cycle. We review the distinct H3 variants' specific features along with their escort partners, the histone chaperones, compiled across different species to discuss their distinct importance considering evolution. We place H3 dynamics at different times during the cell cycle with the possible consequences for genome stability. Finally, we examine how their mutation and alteration impact disease. The emerging picture stresses key parameters in H3 dynamics to reflect on how when they are perturbed, they become a source of stress for genome integrity.

Citing Articles

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.

Basic Epigenetic Mechanisms.

Davie J, Sattarifard H, Sudhakar S, Roberts C, Beacon T, Muker I Subcell Biochem. 2025; 108():1-49.

PMID: 39820859 DOI: 10.1007/978-3-031-75980-2_1.

Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression.

Jin Y, Liang G, Li R, Wang S, Alnouri M, Bentsen M Nat Cardiovasc Res. 2025; 4(2):180-196.

PMID: 39779823 PMC: 11825370. DOI: 10.1038/s44161-024-00593-y.

InTraSeq: A Multimodal Assay that Uncovers New Single-Cell Biology and Regulatory Mechanisms.

Beausoleil S, Ariss M, Huang L, Ding X, Sheth S, Levy T Res Sq. 2024; .

PMID: 39711533 PMC: 11661302. DOI: 10.21203/rs.3.rs-5284652/v1.

Multi-omics approaches reveal that diffuse midline gliomas present altered DNA replication and are susceptible to replication stress therapy.

Hains A, Chetal K, Nakatani T, Marques J, Ettinger A, Junior C Genome Biol. 2024; 25(1):319.

PMID: 39707510 PMC: 11660928. DOI: 10.1186/s13059-024-03460-y.

References

Khazaei S, Chen C, Andrade A, Kabir N, Azarafshar P, Morcos S . Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration. Cell. 2023; 186(6):1162-1178.e20. PMC: 10112048. DOI: 10.1016/j.cell.2023.02.023. View

Riera A, Barbon M, Noguchi Y, Reuter L, Schneider S, Speck C . From structure to mechanism-understanding initiation of DNA replication. Genes Dev. 2017; 31(11):1073-1088. PMC: 5538431. DOI: 10.1101/gad.298232.117. View

Renaud-Pageot C, Quivy J, Lochhead M, Almouzni G . CENP-A Regulation and Cancer. Front Cell Dev Biol. 2022; 10:907120. PMC: 9201071. DOI: 10.3389/fcell.2022.907120. View

English C, Adkins M, Carson J, Churchill M, Tyler J . Structural basis for the histone chaperone activity of Asf1. Cell. 2006; 127(3):495-508. PMC: 2981792. DOI: 10.1016/j.cell.2006.08.047. View

Arunkumar G, Melters D . Centromeric Transcription: A Conserved Swiss-Army Knife. Genes (Basel). 2020; 11(8). PMC: 7463856. DOI: 10.3390/genes11080911. View

Sharma A, Dimitrov S, Hamiche A, Van Dyck E . Centromeric and ectopic assembly of CENP-A chromatin in health and cancer: old marks and new tracks. Nucleic Acids Res. 2018; 47(3):1051-1069. PMC: 6379705. DOI: 10.1093/nar/gky1298. View

Chan K, Fang D, Gan H, Hashizume R, Yu C, Schroeder M . The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013; 27(9):985-90. PMC: 3656328. DOI: 10.1101/gad.217778.113. View

SHELBY R, Monier K, Sullivan K . Chromatin assembly at kinetochores is uncoupled from DNA replication. J Cell Biol. 2000; 151(5):1113-8. PMC: 2174364. DOI: 10.1083/jcb.151.5.1113. View

Ricketts M, Dasgupta N, Fan J, Han J, Gerace M, Tang Y . The HIRA histone chaperone complex subunit UBN1 harbors H3/H4- and DNA-binding activity. J Biol Chem. 2019; 294(23):9239-9259. PMC: 6556585. DOI: 10.1074/jbc.RA119.007480. View

10.

Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y . Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell. 2004; 116(1):51-61. DOI: 10.1016/s0092-8674(03)01064-x. View

11.

Voon H, Hughes J, Rode C, de la Rosa-Velazquez I, Jenuwein T, Feil R . ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes. Cell Rep. 2015; 11(3):405-18. PMC: 4410944. DOI: 10.1016/j.celrep.2015.03.036. View

12.

Drane P, Ouararhni K, Depaux A, Shuaib M, Hamiche A . The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 2010; 24(12):1253-65. PMC: 2885661. DOI: 10.1101/gad.566910. View

13.

Ray-Gallet D, Almouzni G . The Histone H3 Family and Its Deposition Pathways. Adv Exp Med Biol. 2020; 1283:17-42. DOI: 10.1007/978-981-15-8104-5_2. View

14.

Gunjan A, Verreault A . A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Cell. 2003; 115(5):537-49. DOI: 10.1016/s0092-8674(03)00896-1. View

15.

Rouillon C, Eckhardt B, Kollenstart L, Gruss F, Verkennis A, Rondeel I . CAF-1 deposits newly synthesized histones during DNA replication using distinct mechanisms on the leading and lagging strands. Nucleic Acids Res. 2023; 51(8):3770-3792. PMC: 10164577. DOI: 10.1093/nar/gkad171. View

16.

Shrestha R, Ahn G, Staples M, Sathyan K, Karpova T, Foltz D . Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. Oncotarget. 2017; 8(29):46781-46800. PMC: 5564523. DOI: 10.18632/oncotarget.18108. View

17.

Franklin S, Zweidler A . Non-allelic variants of histones 2a, 2b and 3 in mammals. Nature. 1977; 266(5599):273-5. DOI: 10.1038/266273a0. View

18.

Gershman A, Sauria M, Guitart X, Vollger M, Hook P, Hoyt S . Epigenetic patterns in a complete human genome. Science. 2022; 376(6588):eabj5089. PMC: 9170183. DOI: 10.1126/science.abj5089. View

19.

Jang C, Shibata Y, Starmer J, Yee D, Magnuson T . Histone H3.3 maintains genome integrity during mammalian development. Genes Dev. 2015; 29(13):1377-92. PMC: 4511213. DOI: 10.1101/gad.264150.115. View

20.

Mohammad F, Helin K . Oncohistones: drivers of pediatric cancers. Genes Dev. 2018; 31(23-24):2313-2324. PMC: 5795778. DOI: 10.1101/gad.309013.117. View