Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset.
Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset.
复制标题
揭示 APC-Cdh1 在产生 S 期开始动态中的作用。
DOI：
10.1091/mbc.e13-08-0480
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发表时间：
2014
影响因子：
3.3
通讯作者：
Pomerening,JosephR
中科院分区：
文献类型：
--
作者：
Yuan,Xi;Srividhya,Jeyaraman;DeLuca,Thomas;Lee,Ju-HyongE;Pomerening,JosephR
Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes early S-phase onset in conjunction with increase in Rb/E2F1-mediated cyclin E1 expression, but reduced levels of cyclin E1 protein promote this transition. We hypothesize that this is due to a weakened cyclin-dependent kinase inhibitor (CKI)–cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1–mediated proteolysis of Skp2. Indeed, Cdh1 depletion increases Skp2 abundance while diminishing levels of the CKI p27. This lowers the level of cyclin E1 needed for S-phase entry and delays cyclin E1 proteolysis during S-phase progression while corresponding to slowed replication fork movement and reduced frequency of termination events. In summary, using both experimental and computational approaches, we show that APC-Cdh1 establishes a stimulus–response relationship that promotes S phase by ensuring that proper levels of p27 accumulate during G1 phase, and defects in its activation accelerate the timing of S-phase onset while prolonging its progression.
