Impact of p53 isoform ∆133p53 on telomere dynamics and in the induction of genomic instability

Responsable du Stage :Dr Lauréline ROGER

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Résumé du Projet de Stage 

Telomeres are nucleoprotein structures that cap and protect the natural ends of linear chromosomes. One of their main functions is to prevent chromosome extremities from being recognized as DNA double strand breaks (DSB) by the DNA repair machinery. In human somatic cells, telomeres shorten at each cell division because of the incomplete replication of linear chromosomes. Telomere erosion ultimately leads to a partial loss of telomere function and triggers a p53/Rb-dependent stable cell cycle arrest, called senescence. In the absence of fully functional DNA damage check-points, telomeres keep shortening, with ongoing cell divisions, up to a length at which they become dysfunctional and can fuse with other telomeres or non-telomeric loci. Telomere fusions result in a state of genomic instability and massive cell death, known as telomere crisis, which may contribute to the acquisition of large-scale genomic rearrangements and cancer progression.

P53 is known as “the guardian of the genome”. It is a key regulator of cellular stress response and regulates the expression of more than 3,000 genes. To date, 12 isoforms of p53 have been identified in humans. P53 isoforms can act as regulators of p53 by a dominant negative effect but they also may exert gain of function activities. Several p53 isoforms are overexpressed in cancers, however their role and functions are still not well understood. The p53 isoform that we are interested in is called delta133p53. It is involved in the regulation of p53 activity and can inhibit p53 by a dominant negative effect. Overexpression of ∆133p53 isoform in normal human primary cells leads to a bypass of senescence and an extension of proliferative lifespan until the cells eventually die. The bypass of senescence in these cells is associated with an increase in genomic instability. In this context, the goal of this internship will be to study the impact of ∆133p53 on telomere dynamics (telomere length and fusions) and to decipher the mechanisms by which ∆133p53 induces genomic instability.

Address : MNHN / CNRS UMR 7196 / INSERM U1154 – Structure and instability of genomes – 43 Rue Cuvier 75005 Paris