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.

Keywords: DNA replication; cell cycle; chromatin organization.

Figure 1. Chromatin modifiers mediate interactions at replication origins

During interphase, chromatin in the nucleus is packed in chromosome territories (represented by distinct colors). Chromosomes are anchored by the nuclear lamina (orange fibers) with particular chromosomal regions interacting with lamina-associated (green) and other structural proteins (yellow). These interactions anchor intra-chromosomal loops held together by replication-associated protein complexes (purple) that could facilitate distal interactions among replication origins and regulatory regions (orange and blue lines - inset) to initiate DNA replication.