Nucleosome assembly and genome integrity

Abstract

Maintaining the stability of the replication forks is one of the main tasks of the DNA damage response. Specifically, checkpoint mechanisms detect stressed forks and prevent their collapse. In the published report reviewed here we have shown that defective chromatin assembly in cells lacking either H3K56 acetylation or the chromatin assembly factors CAF1 and Rtt106 affects the integrity of advancing replication forks, despite the presence of functional checkpoints. This loss of replication intermediates is exacerbated in the absence of Rad52, suggesting that collapsed forks are rescued by homologous recombination and providing an explanation for the accumulation of recombinogenic DNA damage displayed by these mutants. These phenotypes mimic those obtained by a partial reduction in the pool of available histones and are consistent with a model in which defective histone deposition uncouples DNA synthesis and nucleosome assembly, thus making the fork more susceptible to collapse. Here, we review these findings and discuss the possibility that defects in the lagging strand represent a major source of fork instability in chromatin assembly mutants.

Keywords: :

• Asf1
• H3K56 acetylation
• Okazaki fragment
• Rad27
• genetic instability
• homologous recombination
• nucleosome assembly
• replication fork

This article refers to:

Note

A work that demonstrates a interconnection between lagging-strand synthesis and chromatin assembly was published while this manuscript was in press.⁴⁸

Acknowledgments

We thank J.C. Reyes and R.E. Wellinger for critical reading of the manuscript. The research was funded by the Spanish Ministry of Science (BFU2009-09036).