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Review
. 2013 Aug 1;5(8):a010207.
doi: 10.1101/cshperspect.a010207.

Chromatin and DNA Replication

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Free PMC article
Review

Chromatin and DNA Replication

David M MacAlpine et al. Cold Spring Harb Perspect Biol. .
Free PMC article

Abstract

The size of a eukaryotic genome presents a unique challenge to the cell: package and organize the DNA to fit within the confines of the nucleus while at the same time ensuring sufficient dynamics to allow access to specific sequences and features such as genes and regulatory elements. This is achieved via the dynamic nucleoprotein organization of eukaryotic DNA into chromatin. The basic unit of chromatin, the nucleosome, comprises a core particle with 147 bp of DNA wrapped 1.7 times around an octamer of histones. The nucleosome is a highly versatile and modular structure, both in its composition, with the existence of various histone variants, and through the addition of a series of posttranslational modifications on the histones. This versatility allows for both short-term regulatory responses to external signaling, as well as the long-term and multigenerational definition of large functional chromosomal domains within the nucleus, such as the centromere. Chromatin organization and its dynamics participate in essentially all DNA-templated processes, including transcription, replication, recombination, and repair. Here we will focus mainly on nucleosomal organization and describe the pathways and mechanisms that contribute to assembly of this organization and the role of chromatin in regulating the DNA replication program.

Figures

Figure 1.
Figure 1.
Histone dynamics at the replication fork. New and parental histones are incorporated into chromatin behind the replication fork. The disassembly of nucleosomes ahead of the replication fork provides a parental pool of H3–H4 tetramers or dimers for assembly by histone chaperones. Newly synthesized dimers of H3–H4 histones are also deposited at the fork. The recycling of parental histones provides a means to maintain and propagate distinct chromatin states. H2A–H2B dimers are assembled into chromatin following the deposition of the H3–H4 tetramer.
Figure 2.
Figure 2.
Chromatin assembly is mediated by a network of histone chaperones. Disruption of chromatin in front of the fork aided by ATP-dependent chromatin remodeling activities and the Mcm2–7 helicase results in release of parental histones. Interactions between the Mcm2–7 complex and the histone chaperones ASF1 and FACT may aid in the disassembly of the nucleosome and provide a means for sequestering parental histones at the fork. ASF1 may function in a histone chaperone “assembly line” to split (H3–H4)2 tetramers into H3–H4 dimers (1) for deposition by CAF-1 on either the leading or lagging strand (2). CAF-1 is tethered to the leading and lagging strands via an interaction with PCNA, thereby providing a potential mechanism for semiconservative deposition of parental histones. Similarly, FACT would facilitate the retention and assembly of H2A–H2B dimers onto the nascent DNA (3). Newly synthesized histone H3–H4 dimers are delivered to the replication fork by ASF1 for deposition by CAF-1 (4) or, in the case of histone H2A–H2B dimers, by NAP1 (5).
Figure 3.
Figure 3.
Partitioning of parental and newly synthesized histones. The deposition of newly synthesized histones or parental histones with existing PTMs can affect the inheritance and maintenance of specific chromatin states. Following disruption of nucleosomes at the replication fork, there are three possible outcomes for the deposition of parental and newly synthesized histones in the reassembled chromatin: deposition of parental H3–H4 only, deposition of mixed H3–H4 molecules composed of parental and nascent histones, or deposition of only newly synthesized H3–H4. On disassembly of the parental nucleosome, the (H3–H4)2 tetramer can either remain intact (1) or split into two H3–H4 dimers (2). Deposition of the (H3–H4)2 tetramer or deposition of two parental H3–H4 dimers followed by addition of two H2A–H2B dimers will result in the inheritance of a nucleosome with a parental H3–H4 tetramer core. Alternatively, the split H3–H4 dimers may associate with newly synthesized H3–H4 dimers (3), resulting in a nucleosome with a mixed H3–H4 tetramer core. Finally, the deposition of two newly synthesized H3–H4 dimers (4) will result in a nucleosome devoid of any parental histone PTMs.
Figure 4.
Figure 4.
Nucleosome organization at origins of replication. The AT-rich nature of the ACS and flanking sequences at S. cerevisiae origins of replication prevent encroachment of nucleosomes into the origin. The nucleosome-free region at origins of replication is observed in yeast and higher eukaryotes and may function as a primary determinant for ORC binding. On ORC binding the flanking nucleosomes become precisely positioned, and this positioning is dependent on ORC and an ATP-dependent chromatin remodeling activity. The nucleosome-free region at the origin may facilitate the loading of multiple Mcm2–7 complexes and subsequent DNA unwinding events before initiation.

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