Role of BRCA1 and BARD1 Phosphorylation in Response to DNA Damage in Caenorhabditis elegans Meiosis

• Autores: Nuria Fernández Fernández
• Directores de la Tesis: Tatiana García Muse (dir. tes.)
• Lectura: En la Universidad de Sevilla ( España ) en 2026
• Idioma: inglés
• Número de páginas: 126
• Enlaces
  • Tesis en acceso abierto en: IdUS
• Resumen

  • DNA is constantly exposed to endogenous and exogenous sources of DNA damage that threaten genome stability. During meiosis, accurate repair of DNA double-strand breaks (DSBs) is essential for crossover (COs) formation and faithful chromosome segregation. Errors in these processes can lead to aneuploidy, a maximum degree of genome instability related to infertility and genetic syndromes. The DNA Damage Response (DDR) preserves genome integrity through a network of signalling and repair pathways coordinated by the kinases ATM and ATR, which phosphorylate serine/threonine residues within SQ/TQ motifs on target proteins. Despite extensive knowledge of DDR in somatic cells, how these mechanisms function in the germline remains less understood. Using Caenorhabditis elegans as a model, this study investigated how post-translational modification of the BRCA1–BARD1 complex (BRC-1/BRD-1) contributes to the meiotic DDR. We identified DNA damage–induced phosphorylation of the BRC-1 and BRD-1 and we generated non-phosphorylatable brc-1 and brd-1 alleles using CRISPR–Cas9 genome editing technique. These mutants displayed normal meiotic progression under physiological conditions but exhibited pronounced sensitivity to ionizing radiation (IR), DSBs accumulation and aberrant diakinesis nuclei. Loss of HIM-6/BLM and MUS-81, which mediate the dissolution and resolution of recombination intermediates respectively, partially abolished the aberrant diakinesis phenotypes in BRC-1 non-phosphorylatable mutant. Hence, in this thesis we propose that phosphorylation of BRC-1/BRD-1 in response to ionizing radiation-induced DSBs constitutes a key regulatory step that ensures the proper resolution of recombination intermediates, preserving germline integrity and genomic stability.