Figure 7. GNL3 prevents resection of stalled replication forks by sequestrating ORC2 in the nucleolus.

1. HU‐treatment stalls active replication forks and activate dormant origins. When GNL3 is impaired, more origins may be licensed increasing the probability of replication origin firing. This could lead to over replication and replication stress. When GNL3‐deficient cells are treated with HU, the number of targets for HU is increased leading to activation of more dormant origins, a situation that leads to the exhaustion of the pool of available RPA that may explain the resection of nascent DNA. Inhibition of origin firing with CDC7 inhibitor, roscovitine or depletion of MCM3 counteracts this effect.
2. Thanks to its ability to accumulate into the nucleolus, GNL3 may sequester a subset of ORC2 to precisely regulate origin licensing. When GNL3 is depleted (siGNL3) or does not accumulate in the nucleolus, ORC2 is released into the nucleoplasm leading to more licensed origins and DNA resection upon HU treatment.