Structure of a human replisome shows the organisation and interactions of a DNA replication machine.
Structure of a human replisome shows the organisation and interactions of a DNA replication machine.
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DOI：
10.15252/embj.2021108819
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Yeeles JTP
中科院分区：
文献类型：
--
作者：
Jones ML;Baris Y;Taylor MRG;Yeeles JTP
人类复制体是负责精确染色体复制的分子机器的精细排列。其核心是CDC 45-MCM-GINS（CMG）解旋酶，除了解旋亲本DNA双链体外，还排列许多蛋白质，包括前导链聚合酶Pol ε，以及TIMELESS-TIPIN，CLASPIN和AND-1，这些蛋白质在维持顺利的复制体进展中具有关键和不同的作用。这些蛋白质在人类复制体中是如何协调的还知之甚少。我们已经确定了包含CMG、Pol ε、TIMELESS-TIPIN、CLASPIN和AND-1的与复制叉DNA结合的人复制体的3.2 μ m cryo-EM结构。该结构允许详细了解AND-1，TIMELESS-TIPIN和Pol ε如何接合CMG，揭示CLASPIN如何结合多个复制体组分并确定Pol ε催化结构域的位置。此外，MCM亚基和TIMELESS-TIPIN与复制叉DNA形成的复杂接触网络表明了链分离的机制。重组人核心复制体的冷冻电镜结构显示了TIMELESS-TIPIN、AND-1、Pol ε和CLASPIN如何与CMG解旋酶结合，并提出了DNA链分离的机制。
The human replisome is an elaborate arrangement of molecular machines responsible for accurate chromosome replication. At its heart is the CDC45‐MCM‐GINS (CMG) helicase, which, in addition to unwinding the parental DNA duplex, arranges many proteins including the leading‐strand polymerase Pol ε, together with TIMELESS‐TIPIN, CLASPIN and AND‐1 that have key and varied roles in maintaining smooth replisome progression. How these proteins are coordinated in the human replisome is poorly understood. We have determined a 3.2 Å cryo‐EM structure of a human replisome comprising CMG, Pol ε, TIMELESS‐TIPIN, CLASPIN and AND‐1 bound to replication fork DNA. The structure permits a detailed understanding of how AND‐1, TIMELESS‐TIPIN and Pol ε engage CMG, reveals how CLASPIN binds to multiple replisome components and identifies the position of the Pol ε catalytic domain. Furthermore, the intricate network of contacts contributed by MCM subunits and TIMELESS‐TIPIN with replication fork DNA suggests a mechanism for strand separation. Cryo‐EM structures of reconstituted human core replisomes show how TIMELESS‐TIPIN, AND‐1, Pol ε and CLASPIN engage the CMG helicase, and suggest a mechanism for DNA strand separation.
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影响因子：
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作者：
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