Tesis doctoral de Paula Gutierrez Martinez
During lifetime, dna encounters many types of damage, both from endogenous and%&/exogenous sources. Most lesions are detected and repaired without compromising the life of the%&/cells. However, there are special types of damage that constitute a threat to the integrity of the%&/genome. Double strand breaks (dsb) are the most deleterious lesions that dna can suffer. On%&/one hand, broken dna is a potential source of mutations and chromosomal rearrangements,%&/which can lead to the development of cancer. On the other hand, and if the amount of damage is%&/over a certain threshold, cells can activate apoptotic and/or senescence programs, which can%&/compromise the regenerative ability of tissues and lead to ageing related pathologies. So, the%&/integrity of the genome is a crucial event in the life of every cell. However, unlike proteins and%&/other ¿life molecules¿, dna is not replaced. Thus, proper detection of dna damage, precise%&/signaling and potent repair machineries are needed. The response that cells establish upon dna%&/damage is what we call the dna damage response (ddr). Protein kinases such as atm and%&/atr are key activators of this transduction pathway. Despite their differences, both share the same%&/objective: start a phosphorylation cascade in order to establish the g1/s, intras and g2/m%&/checkpoints, which allow the cell time for repair. However, there is evidence that transduction%&/cascades besides phosphorylation are also triggered by the lesion. Accordingly, it is becoming%&/increasingly clear that other posttranslational modifications are crucial for proper maintenance of%&/genomic integrity. Using different mouse models and approaches, we have investigated the role of%&/two signaling pathways ¿phosphorylation and sumoylation- in the maintenance of genomic%&/integrity. Regarding phosphorylation, we have studied the role of chk1, atr¿s main effector%&/kinase, in the response to replicative stress (rs), a poorly understood type of damage that arises%&/from every replication. Regarding sumoylation, we have studied the role of a novel e3 sumo%&/ligase known as mms21 which was thought to be involved in homologous recombination (hr)%&/repair, but which was completely unexplored in mammalian systems. Briefly, we have demonstrated%&/that a third copy of the chk1 gene can protect from the ageing caused by rs in a mouse model of%&/the seckel syndrome. In addition, we present the first evidence to show that the genome protection%&/provided by the mms21/smc5/smc6 complex protects from tumor development in mammals.%&/Altogether, this work offer novel insights about how the signaling of dna damage ¿by%&/phosphorylation or sumoylation- impacts of the onset of ageing and/or cancer.
Datos académicos de la tesis doctoral «La fosforilación y la simoilación en la protección frente al envejecimiento y el cáncer«
- Título de la tesis: La fosforilación y la simoilación en la protección frente al envejecimiento y el cáncer
- Autor: Paula Gutierrez Martinez
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 28/10/2010
Dirección y tribunal
- Director de la tesis
- capetillo Ruiz Fernández
- Tribunal
- Presidente del tribunal: andrés Aguilera lópez
- Ana Losada valiente (vocal)
- jordi Torres rosell (vocal)
- Manuel Serrano marugán (vocal)