La fosforilación y la sumoilación en la respuesta al daño en el DNA y su papel en la protección frente al envejecimiento y el cáncer

Resumen

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.