Cell Cycle and Genomic Stability

Vanesa Gottifredi - Fundación Instituto Leloir


Our body is made up of independent units called cells. Thanks to a "recipe" written in its DNA (deoxyribonucleic acid), each cell has autonomy of function and capacity of duplication. If that recipe is ruined, the cell can die or change. Those changes that promote a continuous increase in cell duplication trigger the disease known as cancer. One of the strategies used to fight cancer is chemotherapy. This treatment creates blots and tachones in the recipe that cause errors in copying and tumor death. Unfortunately, if the cell does not die, it accumulates editions that allow it to escape the toxic effect of the treatment. In those cases a new tumor mass is generated and the treatment stops working. Our laboratory tries to identify mechanisms that favor the escape to chemotherapy, looking for strategies to eliminate them.
Cancer cells are constantly duplicated. Since the efficiency of DNA replication depends to a large extent on the quality of the template DNA, it has been proposed that the reduction of such quality should kill cancer cells. Such a principle is the essence of chemotherapy. Unfortunately, DNA damage is not an exclusive effect of chemotherapy and this causes the result of this treatment to be limited. There is a load of basal DNA damage that is generated from endogenous (for example, oxidative stress) and exogenous (for example, UV radiation) stimuli. Millions of years of evolution have driven the development of a molecular network that helps the successful duplication of damaged molds in healthy cells. Said molecular network guarantees the repair of damaged DNA and promotes its use as a replication template. The cancer cells preserve this network and take advantage of it to survive a chemotherapeutic stimulus. Our laboratory tries to identify central factors of this network, establishing its role in DNA replication, cell survival and genomic stability. We also identify agents that specifically kill cancer cells and then explore the mechanism that triggers cell death. Our objective is to suggest rational modifications that combine chemotherapy with the inactivation of key molecules that facilitate the duplication of cells with a high content of damaged DNA.

Speroni J, Federico MB, Mansilla S, Soria G and Gottifredi V. (2012). A kinase independent role of Chk1 in the replication of damaged DNA. Proc Natl Acad Sci U S A. May 8, 109(19) 7344-9. PubMed

Soria, G., Gottifredi. V. PCNA-coupled p21 degradation after DNA damage: and exception that confirms the rule?DNA repair. 9: 358-364 (2010).     PubMed

Soria, G., Belluscio, L., van Cappellen, W.A., Kanaar, R., Essers, J., Gottifredi, V. DNA damage induced Pol eta recruitment takes place independently of the cell cycle phase. Cell Cycle. 8: 3340-3348 (2009).     PubMed

Prives, C., Gottifredi, V. The p21 and PCNA partnership: a new twist for an old plot. Cell Cycle. 7: 3840-3846 (2008).     PubMed

Soria, G., Speroni, J., Podhajcer, O.L., Prives, C., Gottifredi, V. p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation. J Cell Sci. 121: 3271-3282 (2008).     PubMed

Soria, G., Podhajcer, O., Prives, C., Gottifredi, V. P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation. Oncogene. 25: 2829-2838 (2006).     PubMed

Gottifredi, V., Prives, C. The S phase checkpoint: when the crowd meets at the fork. Semin Cell Dev Biol. 16: 355-368 (2005).     PubMed

Gottifredi, V., McKinney, K., Poyurovsky, M. V., and Prives, C. (2004). Decreased p21 levels are required for efficient restart of DNA synthesis after S phase block. J Biol Chem 279, 5802-5810. PubMed

Gottifredi, V., and Prives, C. (2001). Molecular biology. Getting p53 out of the nucleus. Science 292, 1851-1852. IF: 23,32 PubMed

Gottifredi, V., Shieh, S., Taya, Y., and Prives, C. (2001). p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc Natl Acad Sci U S A 98, 1036-1041. PubMed

Gottifredi, V., Karni-Schmidt, O., Shieh, S. S., and Prives, C. (2001). p53 down-regulates CHK1 through p21 and the retinoblastoma protein. Mol Cell Biol 21, 1066-1076. PubMed

Vanesa Gottifredi
Head of Laboratory - vgottifredi@leloir.org.ar

Sabrina Mansilla
Research Assistant - CONICET

Marina Alejandra González Besteiro
Research Assitant - CONICET

Julieta Martino
Posdoctoral Fellow - ANPCyT

Natalia Soledad Paviolo
Posdoctoral Fellow - ANPCyT

Sebastián Siri
Posdoctoral Fellow - ANPCyT

Nicolás Calzetta
PhD Fellow - CONICET

María Belén de la Vega Paéz

Sofía Venerus Arbilla

Sofia Loureiro
Predoctoral Fellow

Victoria Pauwels
Predoctoral Fellow