DNA replication timing, genome stability and cancer

Abstract

Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA replication is referred to as the replication-timing program. The replication-timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the replication-timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the replication-timing program is deregulated in many disease states, including cancer. Aberrant DNA replication timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain replication timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of “chromothripsis” and “kataegis”. In this review, we will discuss how the normal replication timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells.

Adamts18 deletion results in distinct developmental defects and provides a model for congenital disorders of lens, lung, and female reproductive tract development

“…(C,D) Higher magnification of retinas from WT (C) and Adamts18 −/− (D) littermates. GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer (Donley and Thayer, 2013); ONL, outer nuclear layer. Scale bar: 200 μm.…”

Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes

“…point mutations, somatic copy number alterations and LOH arise because of erroneous repair of DNA lesions by various DNA repair pathways. Recently, it was reported that local DNA RT also affects the patterns of point mutations (4–6) and copy number alterations (4,7,8)—point mutations are enriched in late replicating regions, and end points of somatic copy number alterations, especially deletions, occur at a high frequency in late replicating regions (10). Here we reported that, in contrast, the LOH end points selectively occur in early replicating regions in multiple cancer types (Figure 2A).…”

“…DNA replication is spatially segregated such that some genomic regions are replicated early and others later during S phase (3). It was recently demonstrated that local DNA replication timing (RT) affects the patterns of point mutations (4–6), somatic copy number alterations (4,7,8) and rearrangements (9) in cancer and normal genomes—late replicating regions accumulate more mutations than early replicating regions (10). These findings prompt the question of whether LOH events, which are primarily replication-dependent phenomena, also show distinct patterns in the context of DNA RT.…”

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

“…If sustained for long periods it can lead to incompletely duplicated chromosomes that could undergo fragmentation or generate chromatin bridges, which in turn sustain chromosome rearrangements or tetraploidy (Burrell et al, 2013; Donley and Thayer, 2013; Russo et al, 2015). …”