Exploring the role of genomic instability in cancer and neurodegenerative disease through mouse models
Author
Nieto Soler, MaríaEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Oncológicas (CNIO)Date
2015-07-28Subjects
Proteínas - Tesis doctorales; Oncogenes - Tesis doctorales; Enfermedades neurodegenerativas - Aspectos genéticos - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 28-07-2015Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
DNA replication stress (RS) is one of the most common and dangerous forms of genotoxic stress, which occurs when the progression of replication forks is halted by endogenous or exogenous lesions. This frequently leads to the accumulation of highly unstable single-stranded DNA (ssDNA). If persistent, RS leads to DNA double-strand breaks (DSBs) and genomic rearrangements that are cell-toxic. The ATR kinase is one of the key players in the response to RS, and triggers the activation of the G2/M checkpoint while it promotes the stability of stalled replication forks. ATR inhibiton leads to an accumulation of RS and impairs checkpoint activation, thereby causing cells to collapse due to mitotic catastrophe.
Investigating the basic mechanisms of RS-driven toxicity and exploring tumors that are especially sensitive to ATR inhibitors constituted the core of the present work. On the first part we have studied the role of FBH1, a DNA helicase thought to mediate the accumulation of ssDNA during RS and to regulate the response to RS-derived breakage. Our study leads to conclude that in mice, the contribution of FBH1 in such processes has a minor impact either in physiological conditions or in a context of defective DNA damage repair. This might be due to compensatory mechanisms or redundant factors that evolved in mammals.
On the second part we explored the role of RS in Ewing sarcomas. These neoplasias bear a translocation between EWSR1 and a transcription factor, most frequently FLI1. Evidence exists that the resulting fusion proteins (most commonly EWS/FLI1) act as oncogenic transcription factors and cause tumorigenesis. Less attention has been put on the actual role of EWS, the product of EWSR1, and how a loss of function of EWS can impact on tumorigenesis. Our work firstly demonstrates that Ewing sarcomas suffer a high degree of RS and therefore are suitable candidates for treatment with ATR inhibitors. Next we demonstrate that R-loops are responsible for RS in Ewing sarcomas, and that R-loop accumulation is caused by the absence of EWS activity. This might be due to a dominant-negative effect of EWS/FLI1 over EWS. Furthermore, we propose a model for EWS R-loop-suppressor function, by which self-aggregation around R-loops promotes R-loop removal. Finally we describe a phenotype of neurodegeneration in adult EWS-depleted mice, which reveals a role for EWS in preventing ALS-linked neurodegeneration.
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