Mechanisms to control rereplication and implications for cancer

Abstract

Recent advances in the replication field have highlighted how the replication initiator proteins are negatively regulated by inhibitor proteins and ubiquitin-mediated degradation in mammalian cells to prevent rereplication. When these regulatory pathways go awry, uncontrolled rereplication ensues and a G2/M checkpoint is evoked to prevent cellular death. Many components of the checkpoints activated by rereplicaton are important for cancer prevention by facilitating DNA damage repair processes. The pathways that prevent rereplication themselves have also recently been implicated in preventing tumorigenesis. Studies from patient tumors, genetically altered mice, and mammalian cell culture suggest that deregulation of replication licensing proteins results in an increase in aneuploidy, chromosomal fusions, and DNA breaks. These studies provide a framework to address how regulators of replication function to maintain genomic stability.

Figure 1

Mechanisms to prevent rereplication in mammalian cells. In the center is the pre-RC which is a pre-requisite for replication initiation. The pathways highlighted with black lines are known to inhibit pre-RC formation and by doing so have been demonstrated to prevent rereplication. The pathways denoted with dashed lines also inhibit pre-RC formation but have not yet been shown to prevent rereplication. The red lightening blot denotes pathways activated by DNA damage. The boxed section shows Emi1 which has been shown to prevent rereplication by stabilizing geminin and cyclinA.

Figure 2

Checkpoints activated upon rereplication. Multiple rounds of replication could give rise to replication origins within replication bubbles which would activate ATR-dependent signaling pathways. Replication fork collision could generate DNA double strand breaks and activate ATM-dependent pathways. Orange stars denote proteins essential for checkpoint activation in response to rereplication. The pink dashed line denotes a hypothetical pathway. The 9-1-1 complex is composed of Rad9-Rad1-Hus1. The MRN complex is made up of Mre11-Rad50-Nbs1.