A nonreplicating chromosome (CRC = 1) is on the left. Small cyan circles denote replication origins, small orange circles denote replication forks, and small light-purple squares with an empty diamond inside denote replication termini. When chromosomal replication becomes rate limiting for growth, bacterial cells are capable of elevating chromosomal replication complexity up to eight. Chromosomal replication complexity: the prokaryotic perspective and the mis-repair complication.Ī. Under these conditions, replication forks move slower, and the cells again have to induce additional replication rounds. The same trick also helps at moderate cell division rates when DNA synthesis is inhibited due to limited DNA precursors or a mutation in the DNA metabolism. To avoid slowing their rapid growth to wait for the lagging chromosomal replication, these bacteria are capable of inducing an extra replication round in the same chromosome to bring up the trailing DNA mass synthesis rate to the cell mass increase rate and CRC to four ( Fig 1A). However, some bacterial cells are capable of dividing two times faster than their minimal chromosomal replication time. Under slow growth conditions, CRC in prokaryotic cells also fluctuates between one and two ( Fig 1A). In the prokaryotic cells, with their (1) unique replication origins (2) defined termination zones and (3) cell division soon after termination of the chromosomal replication, during rapid growth with continuous replication, CRC is simply defined as the origin-to-terminus ratio. At the population level, replication complexity of a eukaryotic chromosome can be measured during synchronized S-phase as the ratio of the copy number of early replication origins to the copy number of chromosomal regions known to replicate late in that particular genome, like human centromeres or yeast telomeres. In the eukaryotic chromosomes, with multiple and alternative replication origins firing once and only once during each cell cycle, CRC becomes two during S-phase and returns to one at the end of it. Limits and Dangers of Elevated Chromosomal Replication ComplexityĬhromosomal replication complexity (CRC) is defined as the ratio of the copy number of the most replicated to the unreplicated regions in the same chromosome. Possible experimental tests of these models are discussed. Moreover, I propose how static replication bubbles could be transformed into tandem duplications, double minutes, or inverted triplications. I suggest how static replication bubbles could be stabilized and speculate that some tandem duplications represent such persistent static bubbles. In both prokaryotes and eukaryotes, replification, via sRF processing, causes double-strand DNA breaks and, with their repair elevating chromosomal rearrangements, represents a novel genome instability factor. To accurately describe the resulting "amplification by overinitiation," I propose a new term: "replification" (subchromosomal overreplication). Remarkably, examples of stable elevated CRC in eukaryotic chromosomes are well known under various terms like "differential replication," "underreplication," "DNA puffs," "onion-skin replication," or "re-replication" and highlight the phenomenon of static replication fork (sRF).
A recent experimental inquiry about the limits of CRC in Escherichia coli revealed two major reasons to avoid elevating it further: (i) increased chromosomal fragmentation and (ii) complications with subsequent double-strand break repair. However, bacteria dividing faster than they replicate their chromosome spike CRC to four and even eight. As the ratio of the copy number of the most replicated to the unreplicated regions in the same chromosome, the definition of chromosomal replication complexity (CRC) appears to leave little room for variation, being either two during S-phase or one otherwise.