Research Project: Nek2A Kinazın Hücre Döngüsüne Özgü Etkileşim Partnerlerinin Belirlenerek Sentrozom Kümelerinin Çözülmesine Etkilerinin Incelenmesi
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Contributors
Funders
ID
TB.00562
Authors
Özcan, Selahattin Can
Researcher
Publications
Prolonged overexpression of PLK4 leads to formation of centriole rosette clusters that are connected via canonical centrosome linker proteins
(Nature Portfolio, 2024) Ayhan, Ceyda Açılan; Canbaz, Ata Alpay; Çiçek, Enes; Kalkan, Batuhan Mert; Özcan, Selahattin Can; KUTTAM (Koç University Research Center for Translational Medicine); Graduate School of Health Sciences; School of Medicine; Yes; GRADUATE SCHOOL OF HEALTH SCIENCES; Research Center; SCHOOL OF MEDICINE
Centrosome amplification is a hallmark of cancer and PLK4 is one of the responsible factors for cancer associated centrosome amplification. Increased PLK4 levels was also shown to contribute to generation of cells with centriole amplification in mammalian tissues as olfactory neuron progenitor cells. PLK4 overexpression generates centriole rosette (CR) structures which harbor more than two centrioles each. Long term PLK4 overexpression results with centrosome amplification, but the maturation of amplified centrioles in CRs and linking of PLK4 induced amplified centrosomes has not yet been investigated in detail. Here, we show evidence for generation of large clustered centrosomes which have more than 2 centriole rosettes and define these structures as centriole rosette clusters (CRCs) in cells that have high PLK4 levels for 2 consecutive cell cycles. In addition, we show that PLK4 induced CRs follow normal centrosomal maturation processes and generate CRC structures that are inter-connected with canonical centrosomal linker proteins as C-Nap1, Rootletin and Cep68 in the second cell cycle after PLK4 induction. Increased PLK4 levels in cells with C-Nap1 and Rootletin knock-out resulted with distanced CRs and CRCs in interphase, while Nek2 knock-out inhibited separation of CRCs in prometaphase, providing functional evidence for the binding of CRC structures with centrosomal linker proteins. Taken together, these results suggest a cell cycle dependent model for PLK4 induced centrosome amplification which occurs in 2 consecutive cell cycles: (i) CR state in the first cell cycle, and (ii) CRC state in the second cell cycle.
Keep calm and carry on with extra centrosomes
(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Ayhan, Ceyda Açılan; Kalkan, Batuhan Mert; Özcan, Selahattin Can; Quintyne, Nicholas J.; Reed, Samantha L.; KUTTAM (Koç University Research Center for Translational Medicine); Graduate School of Health Sciences; School of Medicine; Yes; GRADUATE SCHOOL OF HEALTH SCIENCES; Research Center; SCHOOL OF MEDICINE
Precise chromosome segregation during mitosis is a vital event orchestrated by formation of bipolar spindle poles. Supernumerary centrosomes, caused by centrosome amplification, deteriorates mitotic processes, resulting in segregation defects leading to chromosomal instability (CIN). Centrosome amplification is frequently observed in various types of cancer and considered as a significant contributor to destabilization of chromosomes. This review provides a comprehensive overview of causes and consequences of centrosome amplification thoroughly describing molecular mechanisms. Abstract: Aberrations in the centrosome number and structure can readily be detected at all stages of tumor progression and are considered hallmarks of cancer. Centrosome anomalies are closely linked to chromosome instability and, therefore, are proposed to be one of the driving events of tumor formation and progression. This concept, first posited by Boveri over 100 years ago, has been an area of interest to cancer researchers. We have now begun to understand the processes by which these numerical and structural anomalies may lead to cancer, and vice-versa: how key events that occur during carcinogenesis could lead to amplification of centrosomes. Despite the proliferative advantages that having extra centrosomes may confer, their presence can also lead to loss of essential genetic material as a result of segregational errors and cancer cells must deal with these deadly consequences. Here, we review recent advances in the current literature describing the mechanisms by which cancer cells amplify their centrosomes and the methods they employ to tolerate the presence of these anomalies, focusing particularly on centrosomal clustering.
