Replication forks, chromatin loops and dormant replication origins

Abstract

When DNA replication is slowed down, normally dormant replication origins are activated. Recent work demonstrates that cells adapt by changing the organization of chromatin loops and maintaining the new pattern of origin use in subsequent cell cycles.

Figure 1

A simplified version of the AMPD2 locus is shown, with the primary origin oriGNAI3 on the left and two less efficient origins on the right. During G1, origins are licensed by binding Mcm2-7 (blue, M); when origins fire during S phase, Mcm2-7 provides essential helicase activity at the fork. The cartoons on the right show the chromatin of the locus coiled up and cross-linked to proteins of the nuclear matrix (green dots), forming a 'halo' of DNA around the tethering points. (a) Cells adapted for growth under conditions of slow fork movement. Multiple origins fire in the locus, with all origins having become relatively efficient (large red ovals) to compensate for slow fork movement, and all being associated with matrix proteins. (b) In the first cell cycle after a shift to conditions allowing fast fork progression, the rate of origin firing is decreased, but the relative efficiency and the matrix-association properties of the origins are similar to those seen before the shift. Only in the second cell cycle after the shift do the two relatively inefficient origins become dormant again (small red ovals) and less closely associated with the matrix.