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Author
Molins Colomer, Maite
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Abstract
Dysregulation of cell cycle control mechanisms is an event that is indisputably associated with the appearance of various pathologies, including tumor processes. As the main regulators of the cell cycle, CDKs and cyclins play a central role in this type of process, so it is vitally important to understand the mechanisms responsible for this deregulation.
Almost 40 years ago since the discovery of cyclins, the oscillating proteins were traditionally divided into two groups, "cell cycle" and "transcriptional cyclins", which carry out their functions together with their cyclin-dependent kinase partners (CDKs). Since then, several CDK-cyclin partners have been described, such as the cyclin Y family (CCNY) as an activator of CDK16. Although both proteins have recently been implicated in cancer pathogenesis, it is still unclear how the CDK16/CCNY complex exerts its biological activity [1]. CDK16 is involved in neurite outgrowth [2] and intellectual disorders [3]. Recent studies have demonstrated the indispensable role of CDK16 in tumorigenesis. CDK16 is highly expressed in breast cancer, particularly in triple-negative breast cancer (TNBC) [4]. In turn, CCNY has been implicated in several types of cancer, including glioma [5] and hepatocellular carcinoma [6]. To understand the CDK16/CCNY network, this research group used complementary proteomic approaches to identify substrates of the atypical CCNY/CDK16 complex. The aim of my project is to characterise one of these substrates, called RAP1, to better understand its pathological and physiological significance. RAP1 plays a pleiotropic role in the regulation of a variety of cellular processes, including cellular metabolism, DNA damage response and NF-κB signalling, beyond its canonical telomeric role. In addition, its involvement in oncogenesis, progression and chemoresistance in human cancers has been demonstrated [7]. In this work,
after obtaining the different purified elements of interest, the CDK16-CCNY complex has been shown to exhibit kinase activity in vitro. With the fine-tuning done, it has finally been possible to demonstrate that RAP1 is a substrate in vitro of the CDK16-CCNY complex by means of an in vitro phosphorylation assay.
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