Under normal conditions (when nucleotides were readily available), initiation occurred predominantly at one site within the AMPD2 locus. Only in a few cases did minor sites fire instead. Firing of the dominant origin seems to prevent other nearby origins from initiating replication, as only an origin spaced far from the major origin was used simultaneously.
Cells with limited nucleotide availability, however, replicated from a wider variety of origins. Although the predominant origin was not used as often, simultaneous activation from multiple minor sites was more common. Firing efficiency of competent origins has been attributed mainly to epigenetic controls, including nuclear organization. But Debatisse says “things that are far simpler can also determine the choice of origin, including nucleotide pools. And it's completely reversible from one cell cycle to another.”
A change in origin selection strategy probably equalizes genome replication times. Low nucleotide levels slowed replication fork progression, but the increased number of actively firing origins compensated for this difference, thus resulting in equally long S phases. Now, Debatisse hopes to identify proteins that localize to an origin in a nucleotide-dependent manner. ▪