New histone supply regulates replication fork speed and PCNA unloading

Jakob Mejlvang, Yunpeng Feng, Constance Alabert, Kai J. Neelsen, Zuzana Jasencakova, Xiaobei Zhao, Michael Lees, Albin Sandelin, Philippe Pasero, Massimo Lopes, Anja Groth (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)29-43
Number of pages15
JournalJournal of Cell Biology
Volume204
Issue number1
Early online date30 Dec 2013
DOIs
Publication statusPublished - 6 Jan 2014

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Mejlvang, J., Feng, Y., Alabert, C., Neelsen, K. J., Jasencakova, Z., Zhao, X., Lees, M., Sandelin, A., Pasero, P., Lopes, M., & Groth, A. (2014). New histone supply regulates replication fork speed and PCNA unloading. Journal of Cell Biology, 204(1), 29-43. https://doi.org/10.1083/jcb.201305017