Chromatin Structure and Replication Origins: Determinants of Chromosome Replication and Nuclear Organization

Abstract

The DNA replication program is, in part, determined by the epigenetic landscape that governs local chromosome architecture and directs chromosome duplication. Replication must coordinate with other biochemical processes occurring concomitantly on chromatin, such as transcription and remodeling, to insure accurate duplication of both genetic and epigenetic features and to preserve genomic stability. The importance of genome architecture and chromatin looping in coordinating cellular processes on chromatin is illustrated by two recent sets of discoveries. First, chromatin-associated proteins that are not part of the core replication machinery were shown to affect the timing of DNA replication. These chromatin-associated proteins could be working in concert, or perhaps in competition, with the transcriptional machinery and with chromatin modifiers to determine the spatial and temporal organization of replication initiation events. Second, epigenetic interactions are mediated by DNA sequences that determine chromosomal replication. In this review we summarize recent findings and current models linking spatial and temporal regulation of the replication program with epigenetic signaling. We discuss these issues in the context of the genome’s three-dimensional structure with an emphasis on events occurring during the initiation of DNA replication.

Nuclear pore proteins and the control of genome functions

“…A mutation of the zebrafish ELYS gene reduces Mcm2 chromatin levels and sensitizes tissue progenitors to replication stress, suggesting a potential role for this Nup in the activity of dormant replication origins (Davuluri et al 2008;Gao et al 2011). Although functional links between NPC components and replication origin licensing or firing are unclear, the observations reported above and the strong relationship between chromatin architecture, transcriptional activity, and DNA replication reported (Chakraborty et al 2011;Smith and Aladjem 2014;Therizols et al 2014) make it tempting to speculate that NPC-mediated chromatin organization might affect the licensing or activity of at least a subset of replication origins present in the nuclear periphery.…”

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase

“…Initiation of licensed origins in the ensuing S phase requires stimulation by cell cycle-regulated kinases CDK and DDK (for review, see Labib 2010). The kinetics of initiation at different origins, however, are influenced by local chromatin structure and the subnuclear localization of chromosomal domains, such as subtelomeric and telomeric regions that are heterochromatic, peripherally located, and late-replicating (for review, see Aparicio 2013;Rhind and Gilbert 2013;Smith and Aladjem 2014). Accordingly, histone deacetylases and other chromatin modifiers have been implicated in regulating the timing and efficiency of replication origins in eukaryotic cells (for review, see Smith and Aladjem 2014;Creager et al 2015).…”

Replication origins: determinants or consequences of nuclear organization?

“…A tight coordination of the DNA replication machinery, chromatin remodeling complexes and chromatin modifiers can address these two challenges. In addition, some chromatin-associated proteins establish and maintain replication timing domains and nuclear structure [8]. …”

“…Replication origin activation also involves interactions with structural features intermediate filaments (in particular, lamins), matrix and scaffold attachment sites (MARs and SARs, respectively) and Stabilizing Anti Repressor elements (STARs) [2,8]. MARs are known regulators of CCTC-binding factor (CTCF), a transcriptional repressor that acts in concert with the ring-shaped cohesins to anchor DNA to the nuclear matrix [8] and creating chromatin loops.…”

“…Within each cell type, the order of origin activation reflects gene expression patterns and provides coping mechanisms to address replication stress [7]. The spatial and temporal distribution of replication initiation events respond to changes in chromatin structure to coordinate transcription and chromosome condensation with DNA synthesis [5,8]. Conversely, replication origin sequences can affect chromatin structure and modulate transcriptional efficiency [9].…”