Rol d'ERK5 en la preservació de l'estabilitat genòmica i en el desenvolupament hematopoètic

• Autores: Maria Angulo Ibáñez
• Directores de la Tesis: Manuel Reina del Pozo (dir. tes.), Enric Espel Masferrer (codir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2016
• Idioma: español
• Materias:
  • Ciencias de la vida
    • Biología celular
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development.

    Erk5 is a member of the mammalian mitogen-activated kinase family protein that has been related to cell cycle regulation as well as càncer progression. During mitosis, Erk5 is phosphorylated in a cdk-dependent manner and translocates to the nuclei. Erk5 is necessary for proliferation of breast carcinoma cells, where it contributes to G1/S transition by inhibiting the p21 and p27 cdk inhibitors. The tumourigenicity of Erk5 has been related to its capacity to interact with promyelocytic leukemia protein and inhibit its tumor suppressor activity. By blocking the interaction of promyelocytic leukemia protein and MDM2 Erk5 allows the inhibition of tumor suppressor p53 by MDM2.

    Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.

    In this study, we uncovered important alterations in the nucleotide metabolism of Erk5-deficient cells, which were associated to impaired erythropoiesis in mice and to hypersensitivity of leukemic Jurkat cells to exogenous thymidine as evidenced by DNA damage and apoptosis.