Centro Andaluz de Biología Molecular y Medicina Regenerativa

DNA damage response during meiosis

/Research Groups/DNA damage response during meiosis

Our research interest is the DNA damage response (DDR) during meiosis. We use C. elegans, this nematode is a wonderful model system for meiosis studies and in the last years has proved as a powerful model to understand DDR and genome stability.

   Genomic DNA is under constant attack from both endogenous and exogenous DNA damaging agents. Without proper repair the resulting DNA damages would lead to alteration of genomic structure thus affecting the faithful transmission of genetic information. In addition, defects during meiosis lead to aneuploidy, an extreme kind of genetic instability associated with fertility problems, miscarriages and mental retardation syndromes. Very little is known about the relationship between the meiosis progression and the DNA damage response. Since cells undergoing meiosis during oogenesis stay arrested in meiosis I for long periods of time and therefore vulnerable to DNA lesions we speculated if the increase in genome instability inferred from the increase in aneuploidy that correlates with mother age might be related to defects in DDR during meiosis. Phosphorylation is a key regulator in many processes and therefore an obvious first candidate to analyse, and key kinases of DNA damage checkpoints are ATR and ATM. The aim is to address at the molecular level the biological relevance of the DNA damage dependent phosphorylations observed in silico with the peptide array technique and to determine how ATR/ATM DNA damage phosphorylations contribute to the regulation of different DNA repair pathways, both to ensure genome stability of meiotic cells.

   This knowledge of DDR regulation during meiosis should, therefore, provide important insights into fertility defects diagnosis and may present opportunities for therapeutic intervention.

ORCID: 0000-0002-3195-2261

Researcher ID: F-1339-2016

Scopus: 6506810877

Projects as Principal Investigator:

  • Papel de ATR/ATM en la Respuesta al Daño en el ADN Durante Meiosis (PID2021-123850N). Ministerio de Ciencia e Innovación.
  • Fosforilaciones de ATM/ATR en Respuesta al Daño en el ADN durante meiosis (PGC2018-101099-B-I00). Ministerio de Ciencia, Innovación y Universidades.
  • Fosforilaciones de ATM/ATR en Respuesta al Daño en el ADN (2018/00000498). Ayudas a proyectos precompetitivos Plan Propio US.
  • Ayudas para la gestión de la investigación y de la transferencia del conocimiento (2020/00000690). VI Plan Propio GESTION I.

Articles:

  • Zheleva, A; P. Camino, L; Fernández-Fernández, N; García-Rubio, M; Askjaer, P; García-Muse, T*; Aguilera, A. 2021. C. elegans THSC/TREX-2 deficiency causes replication stress and genome instability. J. Cell Scie. (*corresponding). vol.134: jcs258435.
  • San Martin-Alonso M, Soler-Oliva ME, García-Rubio M, García-Muse T*, Aguilera A*. 2021. Harmful R-loops are prevented via different cell cycle-specific mechanisms. (*co-corresponding). Nat. Comm. Vol.12(1):4451.
  • García-Muse T. 2020. Detection of DSB in C. elegans meiosis. Methods Mol. Biol. 2153:287-293.
  • García-Muse T*, Galindo U, Garcia-Rubio M, Martin JS, Polanowska J, O’Reilly N, Aguilera A*, Boulton SJ*. 2019. A meiotic checkpoint alters repair partner bias to permit inter-sister repair of persistent DSBs. (*co-corresponding). Cell Rep. 26: 775-787
  • Castellano-Pozo M, Santos-Pereira, JM, Rondón, AG, Barroso, S, Andújar, E, Pérez-Alegre M, Garcia-Muse T and Aguilera A. 2013. R-loops are linked to histone H3 Ser10 phosphorylation and chromatin condensation.Mol. Cell 52: 583-590.
  • Castellano-Pozo M, Garcia-Muse T* and Aguilera A. 2012. The Caenorhabditis elegans THO complex is required for the mitotic cell cycle and development. PLoS One 7: e52447. (*corresponding).
  • Castellano-Pozo M , Garcia-Muse T* and Aguilera A*. 2012. R-loops cause replication impairment and genome instability during meiosis. EMBO Rep. 13: 923-9. (*co-corresponding).
  • Dengg M*, Garcia-Muse T*, Salus SS, Gill SS, Ashcroft N, Boulton SJ, and Nilsen H. 2006. Abrogation of the CLK-2/RAD-5 checkpoint leads to tolerance to persistent repair intermediates generated by base-excision repair. EMBO Rep. 10: 1046-1051. (*Joint first).
  • Polanowska J, Martin JS, Garcia-Muse T, Petalcorin, MIR, Boulton, SJ. 2006. A conserved pathway to activate BRCA1-mediated ubiquitylation at DNA damage sites. EMBO Journal 25: 2178-2188.
  • García-Muse T and Boulton SJ. 2005. Distinct modes of ATR activation after replication stress and DNA double-strand breaks in Caenorhabditis elegans. EMBO J. 24: 4345-4355.
  • Castillo-Lluva S*, García-Muse T*, Pérez-Martín J. 2004. A member of the Fizzy-related family of APC activators is regulated by cAMP and is required at different stages of plant infection by Ustilago maydis. J Cell Sci. 117: 4143-56. (*Joint first)
  • García-Muse T, Steinberg G, Pérez-Martín, J. 2004. Characterization of B-type cyclins in the smut fungus Ustilago maydis: roles in morphogenesis and pathogenicity. J Cell Sci. 117(Pt 3): 487-506.
  • García-Muse T, Steinberg G, Pérez-Martín J. 2003. Pheromone-induced G2 arrest in the phytopathogenic fungus Ustilago maydis. Euk. Cell 2(3): 494-500.

Reviews:

  • García-Muse T, Aguilera A. 2019. R Loops from physiological to pathological roles. Cell. 179(3): 604-618.
  • García-Muse T, Aguilera A. 2016. Transcription-replication conflicts: how they occur and how they are resolved. Nat Rev Mol Cell Biol. 17(9): 553-63.
  • Gaillard H, García-Muse T, Aguilera A. 2015. Replication stress and cancer. Nat Rev Cancer 15(5): 276-89.
  • Aguilera A and García-Muse T. 2013. Causes of genome instability. Annu. Rev. Genet. 47: 1-32.
  • Aguilera A and García-Muse T. 2012. R-loops: form transcription by-products to threats to genome stability. Mol. Cell 46: 115-24.
  • Garcia-Muse T, Boulton SJ. 2007. Meiotic recombination in Caenorhabditis elegans. Chromosome Res. 15(5):607-21.

Group leader:
Postdoctorals:
  • Dr. Mariola Chacón Rodríguez
PhD students:
  • Nuria Fernández Fernández
Technicians:
  • Candela Caballero Fernández
  • Laura Ángeles Cantalejo Carrasco