The Role of MTBP as a Replication Origin Firing Factor.
The Role of MTBP as a Replication Origin Firing Factor.
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作者：
在DNA复制过程中完整、忠实地复制染色体DNA是遗传信息保持不变的关键。为了实现这一点，必须精确调节复制起始，即在染色体上产生复制DNA的复杂分子机器。尽管我们对细菌和病毒的DNA复制有深刻的了解，但我们对真核细胞复制起始的分子过程和细胞调控的了解却很少。近年来，纯化的复制起始蛋白在结构和生化方面的研究取得了重大进展。MTBP蛋白（mdm2结合蛋白）是高等多细胞真核生物中最后鉴定的复制起始因子。MTBP是在较简单的真核生物芽殖酵母中发现的Sld7蛋白的对应物。在培养的人类细胞中，MTBP对于复制起始至关重要，并且正在成为控制起始点复制起始信号的分子中继，如起始效率、起始位置和起始时间。我们在此讨论最近的进展，揭示分子起始过程和MTBP的作用。复制起始的起始步骤决定了基因组复制机器，即复制体在何时何地产生。严格控制复制起始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准确和准确地复制一次基因组。复制起始的调控必须确保起始特异性地发生在S期，每个细胞周期中起始点不超过一次，有足够的起始点触发以避免非复制间隙，并且只有在有利的情况下，正确的起始点在正确的时间触发。尽管它对遗传稳态很重要，但只有真核生物复制起始及其细胞调控的主要分子过程才被了解。MTBP蛋白（mdm2结合蛋白）是迄今为止在后生动物细胞中发现的最后一个核心复制起始因子。MTBP是酵母Sld7的同源物。它对于起始激活、复制前复合体（pre-RCs）进入复制体的成熟至关重要，并且正在成为激酶和受调节降解的调控焦点。根据最近的结构和生化研究，我们介绍了MTBP蛋白的结构和细胞功能，揭示了真核起源发射反应的关键分子细节。MTBP在复制和其他细胞过程中的作用是如何相互联系的，并与MTBP对肿瘤发生的贡献有关，这在很大程度上仍不清楚。
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. 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.
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影响因子：
7.7
作者：
De Jesús-Kim L;Friedman LJ;Lõoke M;Ramsoomair CK;Gelles J;Bell SP
通讯作者：
Bell SP
影响因子：
56.9
作者：
Boos, Dominik;Yekezare, Mona;Diffley, John F. X.
通讯作者：
Diffley, John F. X.
影响因子：
12.4
作者：
Agarwal, N.;Tochigi, Y.;Iwakuma, T.
通讯作者：
Iwakuma, T.
DOI：
10.1073/pnas.0911500106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Evrin, Cecile;Clarke, Pippa;Speck, Christian
通讯作者：
Speck, Christian
影响因子：
16.6
作者：
Abid Ali F;Douglas ME;Locke J;Pye VE;Nans A;Diffley JFX;Costa A
通讯作者：
Costa A