The Role of MTBP as a Replication Origin Firing Factor

SIMPLE SUMMARY: Copying the chromosomal DNA completely and faithfully during the process of DNA replication is key to inheriting the genetic information in an unaltered state. To achieve this, replication initiation, which generates the complex molecular machines on the chromosomes that copy the DNA, must be precisely regulated. Despite our profound understanding of bacterial and viral DNA replication, our knowledge about the molecular processes and cellular regulation of replication initiation in eukaryotic cells was surprisingly scarce for a long time. Recently, fundamental progress has been made by studying purified replication initiation proteins structurally and biochemically. The MTBP protein (Mdm2-binding protein) was the last replication initiation factor to be identified in higher multicellular eukaryotes. MTBP is the counterpart of the Sld7 protein found in the simpler eukaryote budding yeast. MTBP is essential for replication initiation in cultured human cells and is emerging as a molecular relay for signals that control replication initiation at origins, such as initiation efficiency, placement and timing. We here discuss recent progress to unravel the molecular initiation processes and the role of MTBP. ABSTRACT: The initiation step of replication at replication origins determines when and where in the genome replication machines, replisomes, are generated. Tight control of replication initiation helps facilitate the two main tasks of genome replication, to duplicate the genome accurately and exactly once each cell division cycle. The regulation of replication initiation must ensure that initiation occurs during the S phase specifically, that no origin fires more than once per cell cycle, that enough origins fire to avoid non-replicated gaps, and that the right origins fire at the right time but only in favorable circumstances. Despite its importance for genetic homeostasis only the main molecular processes of eukaryotic replication initiation and its cellular regulation are understood. The MTBP protein (Mdm2-binding protein) is so far the last core replication initiation factor identified in metazoan cells. MTBP is the orthologue of yeast Sld7. It is essential for origin firing, the maturation of pre-replicative complexes (pre-RCs) into replisomes, and is emerging as a regulation focus targeted by kinases and by regulated degradation. We present recent insight into the structure and cellular function of the MTBP protein in light of recent structural and biochemical studies revealing critical molecular details of the eukaryotic origin firing reaction. How the roles of MTBP in replication and other cellular processes are mutually connected and are related to MTBP’s contribution to tumorigenesis remains largely unclear.