5.5:
Chromosome Replication
During the S phase of the cell cycle, the process of chromosome replication begins simultaneously in each of a cell’s chromosomes at numerous origins of replication.
An origin of replication is a nucleotide sequence that interacts with specialized initiator proteins, called the origin recognition complex, at sites where DNA replication begins.
Defining these origins of replication is difficult. Given the large size of the human genome, for example, an estimated tens of thousands of origins would be necessary to replicate the entire genome in a timely fashion.
In humans, no clear consensus on specific origin sequences has been reached. Instead, it is likely that origins are defined by a combination of nucleotide sequences and chromatin structure.
The length of DNA that spans an origin of replication and its two respective termini of replication, where adjacent replication forks eventually fuse, is called a replicon.
Replication does not occur simultaneously in all of the replicons, however. Different cell types have their own specific timing for initiation of replication, typically in clusters of origins.
DNA replication progresses in this fashion throughout the chromosome until it reaches the telomeres, which have a unique replication process involving the enzyme telomerase, a reverse transcriptase.
At this point in the cell cycle, right before cell division – or M phase, a cell will have effectively doubled its chromosomal mass.
In addition to DNA, histone proteins are critical to the physical structure and function of the eukaryotic chromosome. Thus, during chromosome replication, histone synthesis must happen simultaneously with DNA replication.
The replication forks radiating outwards from the origins of replication disrupt the histone octamers into their subunits.
The newly synthesized histone subunits and old histone subunits are re-assembled into octamers and distributed onto daughter DNA strands. Thus, the histone replicates in a semi-conservative fashion where both old and new histones are segregated randomly to the newly synthesized daughter strands.
5.5:
Chromosome Replication
Before a cell can divide, it must accurately replicate all of its chromosomes, including the DNA and its associated histone and non-histone proteins. This process begins at numerous origins of replication during the S phase of the cell cycle in each of a cell’s chromosomes simultaneously. Certain nucleotides can act as origins of replication, but these sequences are not well defined – especially in complex, multi-cellular, eukaryotic species. The length of DNA that spans an origin of replication and its two respective termini of replication, where adjacent replication forks will eventually fuse, is called a replicon. DNA replication progresses in this fashion, cluster of origins at a time, until it reaches the telomeres, which have their own specialized replication process. At this point, when the cell is in M phase and ready to divide, the cell’s chromosomal mass has effectively doubled.
While DNA replication progresses, new histone proteins are synthesized and new histone core particles are formed. These proteins are just as important to chromosome function as DNA since histones are critical to the physical structure of the chromosome.
Origins of Replication
DNA replication begins at certain nucleotide sequences called origins of replication. These sites interact with specialized initiator proteins that begin the process of DNA separation and replication. Defining and quantifying these sequences has proven difficult, especially in complex, multi-cellular, eukaryotic species. For example, the large size of the human genome would necessitate tens of thousands of origins of replication throughout all of the chromosomes. However, counting these sites is difficult because there is no clear consensus on specific origin sequences. It is likely that origins of replication are defined by a combination of nucleotide sequences, various proteins, and chromatin structure.
Replication of histones
Histones are proteins that are responsible for packaging DNA into chromatin and then into chromosomes. Thus, histones are critical to the physical structure and function of the eukaryotic chromosome. During chromosome replication, new histones must also be synthesized in order to package the new DNA into nucleosomes. As the replication fork moves forward, the new and old histones re-assemble randomly on the daughter cells.
Suggested Reading
- Ramachandran, Srinivas, and Steven Henikoff. "Replicating nucleosomes." Science advances 1.7 (2015): e1500587.
- Prioleau, Marie-Noëlle, and David M. MacAlpine. "DNA replication origins—where do we begin?." Genes & development 30.15 (2016): 1683-1697.
- Leonard AC, Méchali M. DNA replication origins. Cold Spring Harb Perspect Biol. 2013;5(10):a010116. Published 2013 Oct 1. doi:10.1101/cshperspect.a010116
- Greider, Carol W., and Elizabeth H. Blackburn. "Identification of a specific telomere terminal transferase activity in Tetrahymena extracts." cell 43.2 (1985): 405-413.