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Projects. Life and Earth Sciences

Cellular response to blocked breakages of DNA and its role in the pathogenesis of Ataxia-Telangiectasia

Lead Researcher:
Felipe Cortés Ledesma

Research Centre:
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER). Sevilla.

Abstract: 

Felipe Cortés LedesmaAtaxia-Telangiectasia (A-T) is caused by mutations in the ATM gene, and it is the paradigm for a series of genetic human syndromes linked to signalling defects and the repair of DNA breakages. The symptoms of A-T include progressive cerebella ataxia, immunodeficiency, radiosensitivity, hypogonadism and a higher incidence of cancer. The role of ATM as the master regulator of cellular response to DNA breakage is very well defined, and it has been characterised in quite good detail. Nevertheless, its impact on the repair process has traditionally been highly controversial. Our laboratory has recently shown that ATM does play a major role in the repair of DNA breakages, but only when these contain ends that have been blocked and require processing before repair can take place. Additionally, this ATM dependent route contributes to cell survival and the maintenance of genomic stability, which suggests that blocked DNA breaks may be an important factor in the pathogenesis of the disease. This project explores this possibility in detail, determining the specific function of ATM in the repair of blocked DNA breaks, while identifying other factors that may be involved in the process.


Felipe Cortés Ledesma

Scientific track record:

  • Doctoral thesis (Sep. 2000 - Dec. 2006). Genetics Department, University of Seville. Prof. Andrés Aguilera López. Repair of breaks in the double chain by homologous recombination with the chromatic sister.
  • Postdoctoral researcher (Jan. 2007 - Jul. 2010). Genome Damage and Stability Centre (GDSC), University of Sussex (UK). Prof. Keith W. Caldecott
    DNA breaks and topoisomerase.
  • Head researcher (from Jul. 2010). CABIMER, University of Seville - CSIC
    DNA breakage and its pathological implications.

Publication highlights:

  • Álvarez-Quilón et al. (2014) ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nature Communications 5:3347.
  • Gómez-Herreros et al. (2014) TDP2 protects transcription from abortive Topoisomerase 2 activity and maintains normal neural function. Nature Genetics 46:516.
  • Gómez-Herreros et al. (2013) TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genetics 9:e1003370.
  • Cortés-Ledesma et al. (2009) A novel human 5'-thyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461:674-678.

Prizes:

  • EMBO Young Investigator 2014.
  • Young Researcher Prize, Sociedad Española de Bioquímica y Biología Molecular (SEBBM) 2014.


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