Zaffar Eman, Ferreira Pedro, Sanchez-Pulido Luis, Boos Dominik
Molecular Genetics II, Centre for Medical Biotechnology, University of Duisburg-Essen, 45141 Essen, Germany.
Medical Research Council Human Genetics Unit, IGC, University of Edinburgh, Edinburgh EH9 3JR, UK.
Biology (Basel). 2022 May 27;11(6):827. doi: 10.3390/biology11060827.
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.
复制起点处的复制起始步骤决定了基因组复制机器（复制体）在基因组中的产生时间和位置。对复制起始的严格控制有助于促进基因组复制的两项主要任务，即在每个细胞分裂周期中准确无误地复制一次基因组。复制起始的调控必须确保起始仅在S期发生，每个细胞周期中没有起点被激活超过一次，有足够的起点被激活以避免未复制的缺口，并且正确的起点在正确的时间但仅在有利的情况下被激活。尽管其对遗传稳态很重要，但目前仅了解真核生物复制起始的主要分子过程及其细胞调控。MTBP蛋白（Mdm2结合蛋白）是迄今为止在后生动物细胞中鉴定出的最后一个核心复制起始因子。MTBP是酵母Sld7的直系同源物。它对于起点激活、前复制复合物（pre-RCs）成熟为复制体至关重要，并且正逐渐成为激酶和受调控降解作用的调控焦点。鉴于最近的结构和生化研究揭示了真核生物起点激活反应的关键分子细节，我们介绍了对MTBP蛋白结构和细胞功能的最新见解。MTBP在复制和其他细胞过程中的作用如何相互关联以及与MTBP对肿瘤发生的贡献如何相关，目前仍不清楚。
