Centro Andaluz de Biología Molecular y Medicina Regenerativa

Mitochondrial plasticity and replication

Research areas:

-Topoisomerase 1: A ‘double-edged sword’ for genome stability and target cancer treatment
-Ion homeostasis and oxidative stress
-Improved sunlight protection

Topoisomerase 1: A ‘double-edged sword’ for genome stability and target cancer treatment

Chemotherapy is an important approach in the treatment of human cancer. Most of the frontline anti-cancer agents are known to interact with DNA or DNA interacting proteins in order to exert their anti-cancer effects. An example for the latter one is Topoisomease 1, an enzymes that changes the supercoiling of the DNA and are required during transcription, recombination and replication. Topoisomerase 1 (Top1) inhibitors have recently been introduced in the clinical treatment of solid tumors including colon, lung and ovarian carcinomas.

Top1 inhibition is linked to torsional stress and genome instability, and we take advantage of yeast and human cell cultures to understand the factors and molecular processes connected to genome integrity, and hence human disease. This understanding helps us to develop new strategies for the development of ‘intelligent’ Top1 inhibitors and improved treatment of metastatic cancers.

Ion homeostasis and oxidative stress

A characteristic of transition metals is that they exhibit two or more oxidation states. E.g. transition metals are essential co-factors for the function of enzymes involved in oxidative stress defense. This includes the Zn/Cu superoxide dismutase SOD1 needed for the detoxification of reactive oxidative species (ROS), but when mutated can cause amyotrophic lateral sclerosis (ALS).

Mn is another transition metal needed for the activation of Golgi-hosted mannosyltransferases. Cis-Golgi Mn-supply depends on Pmr1, a P-type ATPase required for Mn2+/Ca2+ transport. Mutations in the human PMR1 homolog ATP2C1 leads to skin ulceration, improper keratinocyte adhesion and cancer formation in Hailey-Hailey patients. Interestingly, ATP2C1 can complement for Pmr1 function, making it possible to use yeast as a simple system for Hailey-Hailey disease modeling.

We are interested in the understanding the impact of ion-dependent ROS on mitochondrial function, aging and genome integrity. In addition, we take advantage of yeast-based screening approaches to detect small compounds for human disease treatment (e.g. Hailey-Hailey disease).

Improved sunlight protection

Up to 1 in 5 people will develop skin cancer during their lives, and yearly rates of new cases of deadly forms of skin cancer, such as melanoma, are increasing exponentially in western society. In Europe 32’107 new incidents of melanoma cases are registered per year, with 1’606 new annual incidents in Spain.

In this project we want to provide scientific evidence that flexible UV filters provide superior protection to harmful UV radiation (while at the same time allowing for better tanning), as compared to ‘static’ UV filters that are in use nowadays.

Selected Publications:

A new colorimetric assay for antioxidant capacity and photostability Coloration Technology. Fernández-García, E., Heluani-Gahete, H., Wellinger, R.E. (2016) 132 (3), pp. 195-200

Tuning of glyconanomaterial shape and size for selective bacterial cell agglutination. Cid Martín, J.J., Assali, M., Fernández-García, E., (…), Wellinger, R.E., Fernández, I., Khiar, N. Journal of Materials Chemistry B (2016) 4 (11), pp. 2028-2037

Role for RNA:DNA hybrids in origin-independent replication priming in a eukaroytic system. Stuckey R, García-Rodríguez N, Aguilera A, Wellinger RE. Proc Natl Acad Sci U S A. 2015

Manganese Redistribution by Calcium-stimulated Vesicle Trafficking Bypasses the Need for P-type ATPase Function. García-Rodríguez N, Manzano-López J, Muñoz-Bravo M, Fernández-García E, Muñiz M, Wellinger RE. J Biol Chem. 2015

Yeast as a model system to study metabolic impact of selenium compounds. Herrero E, Wellinger RE. Review: Microbiol Cell. 2015

Methods to study transcription-coupled repair in chromatin. Gaillard H, Wellinger RE, Aguilera A. Methods Mol Biol. 2015

COPII Coat Composition Is Actively Regulated by Luminal Cargo Maturation. Manzano-Lopez J, Perez-Linero AM, Aguilera-Romero A, Martin ME, Okano T, Silva DV, Seeberger PH, Riezman H, Funato K, Goder V, Wellinger RE, Muñiz M. Curr Biol. 2014

Voisset C, García-Rodríguez N, Birkmire A, Blondel M, Wellinger RE. Using yeast to model calcium-related diseases: example of the Hailey-Hailey disease. 2014 Biochim Biophys Acta. Review.

Assali M, Cid JJ, Pernía-Leal M, Muñoz-Bravo M, Fernández I, Wellinger RE, Khiar N. Glyconanosomes: disk-shaped nanomaterials for the water solubilization and delivery of hydrophobic molecules. 2013 ACS Nano

García-Rodríguez N, Díaz de la Loza Mdel C, Andreson B, Monje-Casas F, Rothstein R, Wellinger RE. Impaired manganese metabolism causes mitotic misregulation. 2012 J Biol Chem.

de la Loza MC, Gallardo M, García-Rubio M, Izquierdo A, Herrero E, Aguilera A and Wellinger RE. Zim17/Tim15 Links Mitochondrial Iron-Sulfur Cluster Biosynthesis to Nuclear Genome Stability, 2011. Nucleic Acids Res.

Stuckey R, Díaz de la Loza MC and Wellinger RE. Cellular responses to mitochondrial DNA damage in yeast. In: Mitochondria: Structure, Functions and Dysfunctions; Pp: 709-729, Ed. Ed. O. Svensson, Nova Science Publishers NY; ISBN 978-1-61761-490-3 (2010)

Gaillard H., Wellinger R.E., Aguilera A. Methods to study transcription-coupled repair in chromatin, 2009. Methods Mol Biol. 523:141-59.

de la Loza MC, Wellinger RE*, Aguilera A. Stimulation of direct-repeat recombination by RNA polymerase III transcription, 2009. DNA Repair (Amst). 8(5):620-6. (*corresponding author)

de la Loza MC, Wellinger RE. A novel approach for organelle-specific DNA damage targeting reveals different susceptibility of mitochondrial DNA to the anticancer drugs camptothecin and topotecan, 2009. Nucleic Acids Res. 37(4):e26.

Gaillard H., Wellinger, R. E. and A. Aguilera. A new connection between mRNA biogenesis and export with transcription-coupled repair, 2007. Nucleic Acids Res; 35(12):3893-906.

Fitzgerald DJ, Schaffitzel C, Berger P, Wellinger R, Bieniossek C, Richmond TJ and I. Berger I. Multiprotein expression strategy for structural biology of eukaryotic complexes, 2007. Structure. 15:275-9

Huertas P., Garcia-Rubio, M. L., Wellinger, R. E., Luna R. and A. Aguilera. A hpr1 point mutation that impairs transcription and mRNP biogenesis without increasing recombination, 2006. Mol. Cell. Biol. 26:7451-65

Wellinger, R. E., Prado F. and A. Aguilera. Replication fork progression is impaired by transcription in yeast cells lacking a functional THO-complex, 2006. Mol. Cell. Biol. 26:3327-3334

Wellinger, R. E., and J. M. Sogo. Rad52-independent accumulation of joint circular minichromosomes during S phase in Saccharomyces cerevisiae, 2003. Mol. Cell. Biol. 23:6363-72

Gonzalez-Barrera, S., F. Cortes-Ledesma, R. E. Wellinger, and A. Aguilera. Equal sister chromatide exchange is a major mechanism of double-strand break repair in yeast, 2003. Mol Cell 11:1661-71

Lucchini, R., R.E. Wellinger, and J. M. Sogo. Nucleosome positioning at the replication fork, 2001. EMBO J 20:7294-302

Group leader:
  • Dr. Ralf Wellinger
PhD students:
  • Hayat Heluani Gahete
Master students:
  • Rafael Luis Giner Arroyo