Parvovirus-induced depletion of cyclin B1 prevents mitotic entry of infected cells.
Parvovirus-induced depletion of cyclin B1 prevents mitotic entry of infected cells.
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DOI：
10.1371/journal.ppat.1003891
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发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Pintel DJ
中科院分区：
文献类型：
--
作者：
Adeyemi RO;Pintel DJ
细小病毒在S期开始复制后停止细胞周期进程，并在停滞的细胞中继续复制其基因组延长时间。小鼠细小病毒（MVM）诱导DNA损伤反应，这是病毒复制和诱导S/G2细胞周期阻滞所需的。然而，p21和Chk 1，通常与S期和G2期细胞周期停滞响应于不同的DNA损伤刺激的主要效应子，要么下调，或失活，分别在MVM感染。这表明细小病毒可以通过另一种机制调节细胞周期进程。在这项工作中，我们表明，MVM诱导的，p21和Chk 1独立的，细胞周期阻滞通过两步过程进行，这与其他DNA损伤剂或病毒感染不同。MVM感染在感染早期诱导Chk 2激活，导致与蛋白酶体介导的CDC 25 A降解相关的短暂S期阻滞。这一步骤是有效的病毒复制所必需的;然而，Chk 2激活和CDC 25 A丢失不足以使感染的细胞保持在持续的G2停滞状态，这是这种感染的特征。相反，尽管通常抑制进入有丝分裂的CDK 1磷酸化丧失，但MVM诱导的DDR首先导致靶向错误定位，然后导致细胞周期蛋白B1的显著耗尽，从而直接抑制细胞周期蛋白B1-CDK 1复合物功能并阻止有丝分裂进入。因此，MVM感染使用一种新的策略来确保用于持续病毒复制的假S期、有丝分裂前的核环境。DNA病毒诱导细胞DNA损伤反应，其可以呈现必须克服的对感染的阻断，或者可替代地，可以用于病毒优势。细小病毒是脊椎动物中唯一已知的含有单链线性DNA基因组的病毒，其诱导强有力的DNA损伤反应（DDR），其特征在于促进其复制的细胞周期停滞。我们表明，自主细小病毒的MVM诱导的细胞周期停滞是由一种新的两步机制，确保一个假的S期，有丝分裂前，持续的病毒复制的核环境。这种停滞的一个特征是病毒诱导的关键细胞周期调节因子细胞周期蛋白B1的耗竭。细小病毒是感染包括人类在内的许多脊椎动物物种的重要感染因子，我们的研究对这些病毒如何在宿主细胞中实现生产性感染做出了重要贡献。
Parvoviruses halt cell cycle progression following initiation of their replication during S-phase and continue to replicate their genomes for extended periods of time in arrested cells. The parvovirus minute virus of mice (MVM) induces a DNA damage response that is required for viral replication and induction of the S/G2 cell cycle block. However, p21 and Chk1, major effectors typically associated with S-phase and G2-phase cell cycle arrest in response to diverse DNA damage stimuli, are either down-regulated, or inactivated, respectively, during MVM infection. This suggested that parvoviruses can modulate cell cycle progression by another mechanism. In this work we show that the MVM-induced, p21- and Chk1-independent, cell cycle block proceeds via a two-step process unlike that seen in response to other DNA-damaging agents or virus infections. MVM infection induced Chk2 activation early in infection which led to a transient S-phase block associated with proteasome-mediated CDC25A degradation. This step was necessary for efficient viral replication; however, Chk2 activation and CDC25A loss were not sufficient to keep infected cells in the sustained G2-arrested state which characterizes this infection. Rather, although the phosphorylation of CDK1 that normally inhibits entry into mitosis was lost, the MVM induced DDR resulted first in a targeted mis-localization and then significant depletion of cyclin B1, thus directly inhibiting cyclin B1-CDK1 complex function and preventing mitotic entry. MVM infection thus uses a novel strategy to ensure a pseudo S-phase, pre-mitotic, nuclear environment for sustained viral replication. DNA viruses induce cellular DNA damage responses that can present a block to infection that must be overcome, or alternatively, can be utilized to viral advantage. Parvoviruses, the only known viruses of vertebrates that contain single-stranded linear DNA genomes, induce a robust DNA damage response (DDR) that features a cell cycle arrest that facilitates their replication. We show that the autonomous parvovirus MVM-induced cell cycle arrest is caused by a novel two-step mechanism that ensures a pseudo S phase, pre-mitotic, nuclear environment for sustained viral replication. A feature of this arrest is virally-induced depletion of the critical cell cycle regulator cyclin B1. Parvoviruses are important infectious agents that infect many vertebrate species including humans, and our study makes an important contribution to how these viruses achieve productive infection in host cells.
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影响因子：
30.8
作者：
Falck, J;Petrini, JHJ;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1073/pnas.0504583102
发表时间：
2005-09-20
影响因子：
11.1
作者：
Berthet, C;Raj, K;Beard, P
通讯作者：
Beard, P
影响因子：
5.4
作者：
DeBeeck, AO;CailletFauquet, P
通讯作者：
CailletFauquet, P
影响因子：
6.7
作者：
Adeyemi RO;Landry S;Davis ME;Weitzman MD;Pintel DJ
通讯作者：
Pintel DJ
DOI：
10.1073/pnas.1211525109
发表时间：
2012-08-14
影响因子：
11.1
作者：
Ilves, Ivar;Tamberg, Nele;Botchan, Michael R.
通讯作者：
Botchan, Michael R.