Tesis doctoral de Barbara Martinez Pastor
Dna is the only biological molecule that relies on repair of existing molecules, without any remanufacture. But in the organism, dna, as any other biomolecule, is constantly under insults that result from endogenous (cellular metabolic processes) or exogenous sources (environmental factors). To avoid the accumulation of dna damage and ensure survival and propagation of accurate copies of the genome to subsequent generations, eukaryotic cells respond to dna damage with a multifaceted response: the dna damage response (ddr). atm and atr are two kinases that are key to initiate the signaling of the ddr. At the beginning of this thesis, atm and atr were thought to coordinate two separate and alternative molecular routes in the checkpoint responses: atm would signal dsb in any phase of the cell cycle through its downstream kinase chk2, whereas atr would only be activated by replicative damage and lead to checkpoint activation in a chk1 kinase-dependent manner. Analyzing the requirements of these four kinases in the response to dsb produced by ionizing radiation we discovered that, in this context, both molecular routes are connected. The crosstalk between atm and atr occurs at the level of atr loading on the damaged chromatin, a process that is controlled by atm in response to ionizing radiation. This initial study attracted our research to the role that chromatin plays in the assembly of the ddr. In particular, we decided to explore how the preexisting chromatin configuration could affect the ddr. In this regard, we first discovered that cells with a more ¿open chromatin¿ have an enhanced signaling per break that leads to a more robust ddr and higher resistance to genotoxic agents. Specifically, lower levels of the linker histone h1 lead to a more robust atr-chk1 pathway, which stimulates homologous recombination (hr) mediated repair and longer telomeres. These results prompted us to explore whether we could modulate chromatin accessibility in vivo, in a mammalian model. With this in mind, we generated a mouse model deficient in l3mbtl1, a protein that was previously shown to promote chromatin compaction by bridging distant nucleosomes. Moreover, l3mbtl1 presented a number of features that made it attractive beyond its potential impact on the ddr, such as being a tumour suppressor in drosophila, regulating the e2f/rb and myc transcriptional pathways, or its interaction with hp1 proteins. Our initial data suggest that l3mbtl1 might modulate chromatin accessibility and recombination at specific loci, rather than in a general manner. These and other results about the early characterization of these animals are discussed.
Datos académicos de la tesis doctoral «Estudio del impacto de la estructura de la cromatina en el respuesta a daño en el adn«
- Título de la tesis: Estudio del impacto de la estructura de la cromatina en el respuesta a daño en el adn
- Autor: Barbara Martinez Pastor
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 11/03/2010
Dirección y tribunal
- Director de la tesis
- capetillo Ruiz Fernández
- Tribunal
- Presidente del tribunal: crisanto Gutierrez armenta
- José félix Prado velasco (vocal)
- marcos Malumbres martínez (vocal)
- Ana Losada valiente (vocal)