Erratum to: Controlling the response to DNA damage by the APC/C-Cdh1.

Abstract

Reproduction depends on successful cell division, which is coordinated in the cell cycle. Especially in the context of multicellular organisms, proper control of cell cycle initiation and completion is essential for successful development and homeostasis. Research in the past decades has revealed how cell cycle progression is coordinated by various pathways, which show extensive feedback loops and display multiple levels of cross-talk. Despite this complexity, the core of the cell cycle machinery is constituted by a highly evolutionary conserved molecular ‘engine’, called the cyclin/cyclin-dependent kinase (CDK) complex [1]. Unicellular eukaryotic organisms, such as the budding yeast S. cerevisiae, only have limited genes encoding cyclins and CDKs. In contrast, multicellular organisms, including mammals, express multiple different CDKs, which are often able to bind more than one cyclin, giving rise to a range of distinct cyclin-CDK complexes, each of their activities characterizing discrete phases of the cell cycle. The activity of CDKs is regulated on multiple transcriptional and post-translational levels. CDK activity is, for instance, extensively controlled through activating (e.g. by the CDK-activating kinase (CAK) [2, 3]) and inhibitory phosphorylation (e.g. by the Wee1 and Myt1 kinases [4–6]. However, probably the most important regulatory layer of oscillating CDK activity relates to the controlled production and down-regulation of their cyclin partners, as CDKs are typically only active when bound to a cyclin. The controlled production and down-regulation of cyclins also holds the key as to how the cell cycle can only progress in a unidirectional fashion, and how S-phase and mitosis are limited to once per cell cycle [7]. The timely destruction of cyclin proteins is accounted for by ubiquitin ligation and ensuing degradation by the 26S proteasome [8]. Ubiquitination of mitotic A- and B-type cyclins is accounted for by the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase. During S and G2 phase of the cell cycle, the APC/C remains inactive, which allows the gradual accumulation of mitotic cyclins [9, 10]. Once cells have entered mitosis and have properly aligned their chromosomes, the APC/C is activated and ubiquitinates—among other substrates—mitotic cyclins, and thereby constitutes an important part of the mitotic exit machinery, allowing cells to complete cell division. Through this mechanism, the APC/C forms an integral part of the machinery that ensures periodicity of the cell cycle [8]. Recent evidence has shown that the APC/C also performs additional functions, for instance in response to DNA damage. In this review, we provide a short background on the APC/C and the cellular response to DNA damage. Subsequently, we summarize the current literature on APC/C-Cdh1 activation after DNA damage, and how this affects DNA repair, checkpoint duration and cell fate.