The Inherent Asymmetry of DNA Replication

Abstract

Our understanding of the structure of DNA has helped pave the way for tremendous advancements in understanding the mechanisms of DNA replication. Semiconservative DNA replication has provided an elegant solution to the fundamental problem of how life is able to proliferate in a way that allows cells, organisms, and populations to survive and replicate many times over. Somewhat lost, however, in our admiration for this elegant mechanism is an appreciation for the asymmetries that inevitably occur in the process of DNA replication. As we will discuss in this review, these asymmetries arise as a consequence of the structure of the DNA molecule and the enzymatic mechanism DNA synthesis. Furthermore, increasing evidence suggests that these asymmetries are utilized as mechanisms to drive diverse processes ranging from adaptation and evolution, to cell fate decisions related to patterning and development.

Symmetry from Asymmetry or Asymmetry from Symmetry?

“…However, as discussed here and reviewed in (Snedeker et al, 2017), the inherent asymmetry of DNA replication and the increasing knowledge about the polarity in mitosis raise some questions. Further research will explore whether symmetric outcome arises from tightly regulated asymmetric molecular and cellular processes, or whether symmetry is the default pathway and is then broken by asymmetric processes.…”

“…For example, how stem cells maintain their stemness through many rounds of mitosis has been a long-standing question in the epigenetics field. Our finding that preexisting histones are selectively retained in the renewed stem cell daughter, whereas newly synthesized histones are enriched in the differentiating daughter cell in Drosophila male GSCs suggests that the predominant mechanism of histone recycling may be the conservative model (Snedeker et al, 2017; Tran et al, 2013; Tran et al, 2012; Xie et al, 2015; Xie et al, 2017). Our finding also indicates that the asymmetric epigenome established during DNA replication needs to be recognized and properly segregated by potentially polarized mitotic machinery.…”

Asymmetrical template-DNA strand segregation can explain density-associated mutation-rate plasticity

“…Such asymmetries have been shown to occur during cell division in yeast 11,12 and in E. coli 13 . Furthermore, there is increasing evidence from a broad range of organisms that cells distribute their DNA asymmetrically during each division, in a way supporting the 'Immortal Strand Hypothesis', originally proposed for mammalian stem cells [14][15][16][17][18][19] . According to this hypothesis, adult stem cells have 'Template Strand Co-segregation' (TSC 14,15 ), where the daughter cell maintaining the stem-cell function retains specific 'master' templates of the DNA strands of each chromosome (the parental strands 20 ) at each division, while the differentiating daughter cell receives the new, 'copy' strands.…”

Unidirectional fork movement coupled with strand-specific histone incorporation ensures asymmetric histone inheritance

“…Furthermore, previous studies using biochemistry or high-throughput sequencing methods have not allowed for visualization of histone incorporation pattern at the single-molecule level. Characterizing patterns of histone incorporation during DNA replication in cells under their physiological condition is critical to our understanding of epigenetic regulation in animal development and various diseases, including cancer and tissue dystrophy [reviewed in 32 ].…”