Cell Cycle Control, Maintenance of Genomic Integrity and Carcinogenesis (2307)

Doc.dr. sc. Vjekoslav Dulić
Assoc. Prof. Dr. Sc. Neda Slade, zn. Counsellor

(VD) CRBM-CNRS FRE2593, Montpellier, France
(NS) Ruđer Bošković Institute

Understand the elementary laws by which the cell modulates the apparatus of cell division control in order to preserve the integrity of the genome and the role of positive and negative regulators of the cell cycle in the division with special emphasis on the negative control of the proliferation resulting from genome damage and cell aging.

Introduction to the cell cycle – discovery of the main regulators of cell division in lower and higher eukaryotes
(why did Hartwell, Nurse and Hunt win the Nobel Prize in 2001?).
Cycline-dependent kinases (cyclin dependent kinase - Cdk) and their role in the contote of DNA division and mitosis – positive and negative regulation of cellular proliferation. Cdk inhibitors (CKI: p16Ink4a, p21Waf1, p27Kip1) and tumor suppressants (pRb and p53) – a critical role in the process of stopping cell division.
Negative proliferation control in order to maintain genome integrity – functional relationships between kinases/phosphatases (ATM/ATR, Chk1/2, Cdc25) included in the network of DNA damage detectors (signaling) and cell cycle regulators (Cdk, CKI, p53, pRb).
Cellular aging (senescence) as an anti-tumor barrier: causes and molecular mechanisms
(role of telomerase, " checkpoint " regulators and tumor suppressors, p53 and pRb).

1. Analyze the basic mechanisms behind cell division control, which include a signaling network through which the cell "decides" how to react to genome damage as well as other negative signals.
2. Compare the methods used in the study of cell cycle control and cellular biology (with an emphasis on fluorescent microscopy and immuno-biochemical techniques).
3. Recommend scientific publications to set a new hypothesis about the control of the cell cycle and cellular biology.
4. Assess the relevance of the methods for testing the original hypothesis.

regular attendance, seminar work

Because of the distance, I suggest lectures "on the block". The possibility of co-operation and sending material over the Internet.

1. A book of choice in general cellular biology, e.g. "Molecular Cell Biology" Lodish, Berk.
2. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009 9: 153–166.
3. Bartek J, Lukas J. DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol 2007 19: 238–245
4. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015 14:130-146.
5. Hydbring P, Malumbres M, Sicinski P. Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 2016 17:280-292.
6. Shaltiel IA, Krenning L, Bruins W, Medema RH. The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle. J Cell Sci 2015 128:607-620.
7. Hartwell, L. H. and Weinert, T. A. (1989) Checkpoints: Controls that ensure the order of cell cycle events. Science 246, 629-634.
8. Lundberg, A. S., Hahn, W.C., Gupta, P., and Weinberg, R. A. (2000). Genes involved in senescence and immortalization, Curr Opin Cell Biol 12, 705-9.

Jackson SP, Bartek J. The DNA damage response in human biology and disease. Nature, 2009, 461, 1071–107.
Now I'm having an S, DeCaprio ME. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer 2013 1:585-595.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016 530:184-189.

The success of the course will be evaluated annually by the joint expert committee of the Rudjer Boskovic Institute, the University of Dubrovnik and the University of Osijek, and the leaders will receive information from the participants about the adequacy of the program and performance by the leadership through the survey.