Amplified centrosomes-more than just a threat.

Centrosomes are major organizing components of the tubulin-based cytoskeleton. In recent years, we have gained extensive knowledge about their structure, biogenesis, and function from single cells, cell-cell interactions to tissue homeostasis, including their role in human diseases. Centrosome abnormalities are linked to, among others primary microcephaly, birth defects, ciliopathies, and tumorigenesis. Centrosome amplification, a state where two or more centrosomes are present in the G1 phase of the cell cycle, correlates in cancer with karyotype alterations, clinical aggressiveness, and lymph node metastasis. However, amplified centrosomes also appear in healthy tissues and, independent of their established role, in multi-ciliation. One example is the liver where hepatocytes carry amplified centrosomes owing to whole-genome duplication events during organogenesis. More recently, amplified centrosomes have been found in neuronal progenitors and several cell types of hematopoietic origin in which they enhance cellular effector functions. These findings suggest that extra centrosomes do not necessarily pose a risk for genome integrity and are harnessed for physiological processes. Here, we compare established and emerging 'non-canonical functions' of amplified centrosomes in cancerous and somatic cells and discuss their role in cellular physiology.

Extra centrosomes delay DNA damage-driven tumorigenesis.

Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components, Caspase-2, Raidd/Cradd, or Pidd1. BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.

The SKP2-p27 axis defines susceptibility to cell death upon CHK1 inhibition.

Checkpoint kinase 1 (CHK1; encoded by CHEK1) is an essential gene that monitors DNA replication fidelity and prevents mitotic entry in the presence of under-replicated DNA or exogenous DNA damage. Cancer cells deficient in p53 tumor suppressor function reportedly develop a strong dependency on CHK1 for proper cell cycle progression and maintenance of genome integrity, sparking interest in developing kinase inhibitors. Pharmacological inhibition of CHK1 triggers B-Cell CLL/Lymphoma 2 (BCL2)-regulated cell death in malignant cells largely independently of p53, and has been suggested to kill p53-deficient cancer cells even more effectively. Next to p53 status, our knowledge about factors predicting cancer cell responsiveness to CHK1 inhibitors is limited. Here, we conducted a genome-wide CRISPR/Cas9-based loss-of-function screen to identify genes defining sensitivity to chemical CHK1 inhibitors. Next to the proapoptotic BCL2 family member, BCL2 Binding Component 3 (BBC3; also known as PUMA), the F-box protein S-phase Kinase-Associated Protein 2 (SKP2) was validated to tune the cellular response to CHK1 inhibition. SKP2 is best known for degradation of the Cyclin-dependent Kinase Inhibitor 1B (CDKN1B; also known as p27), thereby promoting G1-S transition and cell cycle progression in response to mitogens. Loss of SKP2 resulted in the predicted increase in p27 protein levels, coinciding with reduced DNA damage upon CHK1-inhibitor treatment and reduced cell death in S-phase. Conversely, overexpression of SKP2, which consequently results in reduced p27 protein levels, enhanced cell death susceptibility to CHK1 inhibition. We propose that assessing SKP2 and p27 expression levels in human malignancies will help to predict the responsiveness to CHK1-inhibitor treatment.