Estudio del papel de la quinasa ATR en envejecimiento y cáncer (desarrollo de un modelo murino)
Advisor
Murga, MatildeEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Oncológicas (CNIO)Date
2010-05-25Subjects
Proteínas quinasas-Tesis doctorales; Células-Envejecimiento-Tesis doctorales; Cáncer-Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leía en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 25-05-2010Abstract
Seckel Syndrome is a rare human disease characterized by growth retardation and
microcephaly. Previous findings have linked Seckel to deficient signalling of the ATR kinase,
which is in charge of safeguarding genomic integrity under conditions of replicative stress. We
have generated a murine model of the disease, bypassing the early lethality of ATR absence, by
means of a humanized allele in which a splicing defect significantly reduces the levels of the
protein. This model, fully recapitulates the symptoms observed in human patients of the
disease; moreover, the analysis of this model has revealed novel disorders derived from a
deficiency in ATR. We not only described these disorders but also tried to understand their
origins and physiological impact. Importantly, Seckel embryos display massive amounts of
replicative stress, which decrease to marginal levels in the tissues of the adult mouse. Despite
this decrease in the amount of stress, mutant mice die early due to the development of a severe
progeroid phenotype, leading us to propose that the replicative stress suffered during
embryogenesis becomes a critical determinant of the lifespan and overall fitness of mammalian
organisms.
The Seckel phenotypes including the progeria were further accelerated in the absence of
p53. The study of the mechanism responsible for this effect suggests a synthetic lethal interaction
between ATR and p53, opening the possibility to study the relevance of using ATR inhibitors for
the selective elimination of p53-deficient tumours. Based upon these observations, we
investigated whether the synthetic lethal effect observed between low ATR levels and p53 loss
were also present in the context of additional cancerous mutations that accelerate replication
rates. To this end, we evaluated the potential role of ATR in the abrogation of lymphomagenesis
induced by c-Myc. Our study suggests that ATR inhibition might be a suitable approach for the
elimination of Myc driven tumours.
Altogether, we here provide the first alive model for ATR studies in a mammal, which
has allowed us to reach important conclusions on the role of replicative stress on cancer and
ageing.
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Google Scholar:Montaña Hoyos, María Fernanda
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