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J Cell Biol. 2014 Jan 6;204(1):29-43. doi: 10.1083/jcb.201305017. Epub 2013 Dec 30.

New histone supply regulates replication fork speed and PCNA unloading.

Author information

1
Biotech Research and Innovation Centre, 2 Centre for Epigenetics, and 3 The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.

Abstract

Correct duplication of DNA sequence and its organization into chromatin is central to genome function and stability. However, it remains unclear how cells coordinate DNA synthesis with provision of new histones for chromatin assembly to ensure chromosomal stability. In this paper, we show that replication fork speed is dependent on new histone supply and efficient nucleosome assembly. Inhibition of canonical histone biosynthesis impaired replication fork progression and reduced nucleosome occupancy on newly synthesized DNA. Replication forks initially remained stable without activation of conventional checkpoints, although prolonged histone deficiency generated DNA damage. PCNA accumulated on newly synthesized DNA in cells lacking new histones, possibly to maintain opportunity for CAF-1 recruitment and nucleosome assembly. Consistent with this, in vitro and in vivo analysis showed that PCNA unloading is delayed in the absence of nucleosome assembly. We propose that coupling of fork speed and PCNA unloading to nucleosome assembly provides a simple mechanism to adjust DNA replication and maintain chromatin integrity during transient histone shortage.

PMID:
24379417
PMCID:
PMC3882791
DOI:
10.1083/jcb.201305017
[Indexed for MEDLINE]
Free PMC Article
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