Triggering mitosis

Abstract

Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein

“…In particular, as depicted in Figure 5 , we identified several mitochondrial SIRT4-interacting proteins and potential substrates (OPA1 [ 42 ]; ATP5F1A [ 34 ]; ANT2 [ 21 ]; IDE [ 52 ]) as well as mostly novel, extra-mitochondrial localized SIRT4 interactors. The latter comprise α- and β-tubulin as subunits of microtubules, components of the centrosomally localized γTURC complex (γ-tubulin, TUBGCP2, TUBGCP3) [ 53 , 54 ] that nucleates microtubules at their minus poles, the microtubule deacetylase HDAC6 that is critically involved in the regulation of microtubule stability and dynamics [ 9 ], and the G 2 /M cell cycle regulator CDK1 [ 55 ]. These SIRT4 interactions were confirmed by nanobody-mediated co-immunoprecipitation ( Figure 5 b and Figure S11 ) and confocal colocalization analyses ( Figure S11 ).…”

Working on Genomic Stability: From the S-Phase to Mitosis

“…The decision to enter mitosis mainly depends on the full activation of the mitotic Cdk1 kinase. This situation is modulated by regulatory mechanisms that interface with other mitotic kinases and checkpoint pathways that safeguard the integrity of the genome before entering mitosis [8][9][10]210]. For example, ATM/ATR checkpoint kinases lead to the degradation of the Cdc25 phosphatases with the consequent inactivation of Cdk1 and cell cycle arrest to block mitosis when DNA repair occurs.…”

“…In addition, increased Cdc25 phosphatase activity is needed to reverse Wee1 dependent CDK inhibition in order to obtain the high CDK activity level necessary to start mitosis at the proper time ( Figure 1). The precise regulation of mitotic CDK complexes at the entry to mitosis has been recently reviewed [8]. Thus, during G2, these positive and negative CDK regulators, whose balance is critical to control high CDK activity and the precise timing of mitosis, are targets of different DNA damage checkpoint pathways that monitor and safeguard the integrity of the genome before reaching the G2/M transition [9,10].…”

Subcellular localization and mitotic interactome analyses identify SIRT4 as a centrosomally localized and microtubule associated protein

“…4, we identified several mitochondrial SIRT4-binding proteins and potential substrates (OPA1 42 ; ATP5F1A 34 ; ANT2 21 ; IDE 48 ) as well as mostly novel, extra-mitochondrial localized SIRT4 interactors. The latter comprise -and -tubulin as subunits of microtubules, components of the centrosomally localized TURC complex (-tubulin, TUBGCP2, TUBGCP3) 49,50 that nucleates microtubules at their minus poles, the microtubule deacetylase HDAC6 that is critically involved in the regulation of microtubule stability and dynamics 9 , and the G2/M cell cycle regulator CDK1 51 . These SIRT4 interactions were confirmed by nanobody-mediated coimmunoprecipitation analyses (Fig.…”