Abstract
DNA replication is a highly coordinated process that is initiated at multiple replication origins in eukaryotes. These origins are bound by the origin recognition complex (ORC), which subsequently recruits the Mcm2-7 replicative helicase in a Cdt1/Cdc6-dependent manner. In budding yeast, two essential replication factors, Sld2 and Mcm10, are then important for the activation of replication origins. In humans, the putative Sld2 homolog, RECQ4, interacts with MCM10. Here, we have identified two mutants of human RECQ4 that are deficient in binding to MCM10. We show that these RECQ4 variants are able to complement the lethality of an avian cell RECQ4 deletion mutant, indicating that the essential function of RECQ4 in vertebrates is unlikely to require binding to MCM10. Nevertheless, we show that the RECQ4-MCM10 interaction is important for efficient replication origin firing.
Highlights
The control of the initiation of DNA replication is important for the timely and faithful duplication of the genome
We observed that the RECQ4-MCM10 complex formed at all stages of the cell cycle and its abundance broadly mirrored that of the level of MCM10 protein (Figure 1B, 1C)
We showed that the interaction between RECQ4 and MCM10 is partially required for viability of chicken cells lacking endogenous RECQ4, and for normal replication origin firing
Summary
The control of the initiation of DNA replication is important for the timely and faithful duplication of the genome. DNA replication initiation occurs in two defined steps, which are conserved amongst vertebrate species. In the first step, conducted prior to S-phase, the origin recognition complex (ORC) binds to specific replication origins. It is possible that other structural features of the DNA define an origin; for example, specific chromatin marks, or the presence of DNA secondary structures in the proximity of the replication origin. The presence of G-quadruplexes has recently been proposed to play an important role in the initiation of DNA replication in chicken cells [2, 3]. The origin-bound ORC directs the recruitment of Cdc and Cdt, which subsequently allows loading of the heterohexameric replicative helicase comprising the Mcm proteins [4, 5]. Origin activation depends on the Cdc7-Dbf (DDK) and
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