Chromatin as a Platform for Modulating the Replication Stress Response

Abstract

Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart.

Keywords: chromatin; chromatin remodeller; genome instability; histone chaperone; replication stress.

Figure 1

A simplified illustration of a replisome on replicating chromatin. The leading strand polymerase POLε associated with the replicative helicase complex (CMG—Cdc45–MCM–GINS) and an RPA-coated lagging strand is shown. The action of ASF1 and CAF-1 in histone deposition, of nascent histone H3–H4 complexes and potentially recycled histones is shown. The histone recycling function of MCM2 and the FACT (Facilitates Chromatin Transcription) complex are shown below. See main text for additional details. CAF-1: Chromatin_assembly factor 1; ASF1: anti-silencing factor 1; PCNA: proliferating cell nuclear antigen; MCM2: minichromosome maintenance 2; POL: DNA polymerase; RPA: replication protein A.

Figure 2

Examples of histone modifications and variants at stalled replication forks. A replication fork stall (orange star) can lead to the exposure of single-stranded DNA (ssDNA) as the helicase separates from the polymerase. This serves as a signal for replication stress which can catalyse local histone modifications or variant incorporation (see main text). Below, five representative outcomes described in this review are shown. In each case, the chromatin-level change is noted at the top and a fork protection and restart protein is recruited to lead to resolution for the stalled fork. In reality these events are certain to be highly coordinated with one another.