The Role of MTBP as a Replication Origin Firing Factor

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.

Dimerization of Firing Factors for Replication Origin Activation in Eukaryotes: A Crucial Process for Simultaneous Assembly of Bidirectional Replication Forks?

“…Moreover, defects in DNA replication caused by deleting the S7M-C domain in MTBP can be rescued by addition of the GST ( G lutathione S - t ransferase) dimerization domain to the MTBP protein lacking its C-terminus [ 40 ]. These suggest that simultaneous activation of the Mcm2–7 double hexamer by the Treslin/Ticrr-MTBP dimer is critical for cell growth in vertebrates (for details, please see the review by Zaffar et al [ 42 ] in this special issue).…”

Cell Cycle-Dependent TICRR/TRESLIN and MTBP Chromatin Binding Mechanisms and Patterns

“…TRESLIN (also known as TICRR) and MTBP are the functional orthologs of the yeast Sld3/Sld7. Despite functional overlaps between TRESLIN/MTBP and Sld3/Sld7, these factors have evolved to accommodate distinct mechanisms of replication control (10, 11, 12, 13, 14). TRESLIN and MTBP are larger and bear little sequence similarity to Sld3 and Sld7 (15, 16, 17, 18).…”

Rif1 restrains the rate of replication origin firing in Xenopus laevis

“…Cyclin- and Dbf4/Drf1-dependent kinases (CDKs and DDKs) activate the pre-RC at the start and during S phase. In budding yeast, Sld7/Sld3, Dbp11 and Sld2 regulate the maturation of the pre-RC into the functional helicase complex Cdc45-MCM-GINS with pol ε (CMGE) in different DDK-CDK-dependent steps (for review, see 10 ). Their respective counterparts in metazoans, MTBP (Mdm2-binding protein)/Treslin, TopBP1 and RecQL4 are loaded onto the pre-RC to build the pre-initiation (pre-IC) complex 11 – 15 .…”