Dimerization of Firing Factors for Replication Origin Activation in Eukaryotes: A Crucial Process for Simultaneous Assembly of Bidirectional Replication Forks?
Dimerization of Firing Factors for Replication Origin Activation in Eukaryotes: A Crucial Process for Simultaneous Assembly of Bidirectional Replication Forks?
复制标题
真核生物复制起始激活激活因子的二聚化：双向复制分叉同时组装的关键过程？
作者：
当细胞分裂时，染色体 DNA 必须忠实地复制并分离到两个子细胞中。 DNA 合成从称为复制起点的特定区域开始。当它启动时，会建立一对复制叉，并且每个复制叉都会远离复制起点。在每个复制叉中，复制解旋酶将 DNA 从双链解旋为单链。这意味着从每个复制起点产生两组活性解旋酶。为了实现这一点，首先将两组复制解旋酶作为非活性二聚体加载到复制起点上。当 S 期特异性细胞周期蛋白依赖性激酶 (S-CDK) 被激活时，无活性的解旋酶在称为激发因子的其他因子的帮助下转化为活性解旋酶。尽管激活两组解旋酶似乎需要两组激发因子，但目前尚不清楚两组激发因子是否同时发挥作用以协调的方式建立双向复制叉。我们在这篇综述中介绍了我们目前对激发因子二聚化的理解，并讨论了它对双向复制叉形成的潜在贡献。控制异六聚体 Mcm2-7 复制解旋酶的活性对于真核生物复制起点活性的调节至关重要。由于双向复制叉是从每个复制起点产生的，因此当起点在 DNA 复制的第一步中被许可进行复制时，两个无活性的 Mcm2-7 异六聚体复合物将作为头对头双六聚体加载在双链 DNA 周围。随后，解旋酶通过“激发”反应被激活，其中 Mcm2-7 双六聚体通过激发因子转化为两个活性解旋酶单元，即 CMG 复合物。激发因子的二聚化可能通过允许同时激活两组解旋酶从而有效组装双向复制叉来促进这一过程。一个例子是激发因子 Sld3/Treslin/Ticrr 通过其结合伙伴 Sld7/MTBP 进行二聚化。在尚未鉴定出 Sld7 直向同源物的生物体中，例如裂殖酵母裂殖酵母，Sld3 本身具有二聚化结构域，并且有人认为这种自我相互作用对于该生物体中的激发反应至关重要。二聚化会引起 Sdl3 的构象变化，这对于点火反应似乎至关重要。此外，Mcm10似乎也受到酵母中自身相互作用的调节。尽管尚不清楚激发因子二聚化在多大程度上有助于真核生物中的激发反应，但我们讨论了激发因子二聚化在同时解旋酶激活中的可能作用。
Chromosomal DNA must be faithfully duplicated and segregated into two daughter cells when cells divide. DNA synthesis initiates from specific regions known as the origins of replication. When it starts, a pair of the replication fork is established, and each replication fork moves away from replication origins. In each replication fork, replicative helicase unwinds DNA from a double to a single strand. This implies that two sets of active helicase are generated from each replication origin. To make this possible, two sets of replicative helicases are loaded onto replication origins as inactive dimers first. When S-phase specific cyclin-dependent kinases, S-CDKs, are activated, the inactive helicase is converted into the active helicase with the aid of other factors called firing factors. Although two sets of firing factors seem to be required to activate two sets of helicase, it is largely unknown whether two sets of firing factors function simultaneously to establish bidirectional replication forks in a coordinated way. We introduce our current understanding of firing factor dimerization and discuss its potential contribution to bidirectional replication fork formation in this review. Controlling the activity of the heterohexameric Mcm2–7 replicative helicase is crucial for regulation of replication origin activity in eukaryotes. Because bidirectional replication forks are generated from every replication origin, when origins are licensed for replication in the first step of DNA replication, two inactive Mcm2–7 heterohexiameric complexes are loaded around double stranded DNA as a head-to-head double hexamer. The helicases are subsequently activated via a ‘firing’ reaction, in which the Mcm2–7 double hexamer is converted into two active helicase units, the CMG complex, by firing factors. Dimerization of firing factors may contribute to this process by allowing simultaneous activation of two sets of helicases and thus efficient assembly of bidirectional replication forks. An example of this is dimerization of the firing factor Sld3/Treslin/Ticrr via its binding partner, Sld7/MTBP. In organisms in which no Sld7 ortholog has been identified, such as the fission yeast Schizosaccharomyces pombe, Sld3 itself has a dimerization domain, and it has been suggested that this self-interaction is crucial for the firing reaction in this organism. Dimerization induces a conformational change in Sdl3 that appears to be critical for the firing reaction. Moreover, Mcm10 also seems to be regulated by self-interaction in yeasts. Although it is not yet clear to what extent dimerization of firing factors contributes to the firing reaction in eukaryotes, we discuss the possible roles of firing factor dimerization in simultaneous helicase activation.
登录
查看更多内容
影响因子：
4.2
作者：
通讯作者：
--
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：
7.7
作者：
Gupta S;Friedman LJ;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：
21.3
作者：
Gambus, A;Jones, RC;Labib, K
通讯作者：
Labib, K