Regulation of Replication Fork Progression Through Histone Supply and Demand

This work shows that the replacement of histones is coordinated with the fork progression during DNA replication. After finding that Asf1, the H3-H4 chaperone, co- purified with the putative helicase MCM2-7 in HeLa cells, the question then was if problems during replication could be the consequence of abnormal chromatin unwinding. This was confirmed by following the cell cycle progression with DNA binding markers and by silencing of Asf1 with siRNAs. Formation of ssDNA was also reduced after Asf1 depletion, i.e.,

[indicating...] that impaired replication reflects a DNA unwinding defect and implied that DNA in chromatin cannot be properly unwound by the replicative helicase. This could reflect a direct effect of Asf1 on DNA unwinding and fork progression or indirect effects, involving DNA damage at the replication fork, replisome collapse, and/or checkpoint signaling. [...] Our results show that replication fork progression is dependent on the histone H3-H4 chaperone, Asf1, and on an equilibrium between histone supply and demand. This dependency could ensure that replication only proceeds when nucleosomes are being formed behind the fork with a proper balance between new and parental histones H3-H4

Model for Asf1 function in replication as a histone acceptor and donor (Groth et al./Science)

Groth A., et al. 2007. Science 318(5858):1928-1931

epigenetics

More comments can be found in the same issue of Science, in the Research Roundup section of the Journal of Cell Biology, and the Faculty of 1000 website.

The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Histone modifications have been found to contribute with certain brain phenomena like memory and behavior, and in this respect, some HDAC inhibitors have been shown to enhance long- term memory, which makes them interesting candidates for treatment of cognitive disorders, particularly phobias, but also for other behavior alterations, like anxiety disorders. In this paper, authors report that sodium valproate (VPA), a HDAC inhibitor, improves the extinction of conditioned fear by enhancing long- term memory in mice, whose effects not only last but are also more pronounced while in training.

When administered prior to training, VPA enhances long- term memory for both the acquisition and extinction of conditioned fear. These findings are consistent with several studies demonstrating that HDAC inhibitors facilitate memory. [...These findings also] support the long- standing view that extinction is new learning and not simply erasure of the original fear association [...].

T. W. Bredy & M. Barad (2008) Learn Mem 15(1):39-45
epigenetics