Regulation of replication fork progression through histone supply and demand.
DNA replication in eukaryotes requires nucleosome disruption ahead of the replication fork and reassembly behind. An unresolved issue concerns how histone dynamics are coordinated with fork progression to maintain chromosomal stability. Here, we characterize a complex in which the human histone chaperone Asf1 and MCM2-7, the putative replicative helicase, are connected through a histone H3-H4 bridge. Depletion of Asf1 by RNA interference impedes DNA unwinding at replication sites, and similar defects arise from overproduction of new histone H3-H4 that compromises Asf1 function. These data link Asf1 chaperone function, histone supply, and replicative unwinding of DNA in chromatin. We propose that Asf1, as a histone acceptor and donor, handles parental and new histones at the replication fork via an Asf1-(H3-H4)-MCM2-7 intermediate and thus provides a means to fine-tune replication fork progression and histone supply and demand.
Groth
Anja
A
Laboratory of Nuclear Dynamics and Genome Plasticity, UMR218 CNRS/Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
Corpet
Armelle
A
Cook
Adam J L
AJ
Roche
Daniele
D
Bartek
Jiri
J
Lukas
Jiri
J
Almouzni
Geneviève
G
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D034622:RNA Interference; D016196:S Phase
C491641:ASF1A protein, human; C491640:ASF1B protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D004277:DNA, Single-Stranded; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D009707:Nucleosomes; D004247:DNA; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2