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Authors
Advisor(s)
Abstract(s)
The final step of cytoplasmic mRNA degradation proceeds in either a 5’-3’ direction,
catalyzed by XRN1, or in a 3’-5’ direction catalyzed by the exosome. In yeast, DIS3/Rrp44
protein is the catalytic subunit of the exosome. In humans, there are three known paralogues of
this enzyme: DIS3, DIS3L1, and DIS3L2. Important findings over the last years have shed a new
light onto the.mechanistic details of RNA degradation by these exoribonucleases. In addition, it
has been shown that they are involved in growth, mitotic control and important human diseases,
including cancer. For example, DIS3L2 inactivation was associated with mitotic abnormalities
and altered expression of mitotic checkpoint proteins (Astuti et al., 2012). In another study, DIS3
was found to be highly expressed in colorectal cancer (CRC), suggesting an oncogenic function
(Camps et al., 2013).
A major challenge in systems biology is to reveal the cellular networks that give rise to
specific phenotypes (Lan et al., 2013). In this project, we aim to analyze how DIS3 and DIS3L1
regulate the human transcriptome, and how their functional interactions modulate the
transcriptional reprogramming of colorectal cancer cells. We will perform an extensive
characterization of the DIS3 and DIS3L1 mRNA targets, using DIS3 and DIS3L1 knockdown and
microarray analysis, in normal colorectal cells, and in different CRC cell lines, in the presence
and absence of stress stimuli, such as hypoxia.
Differential expression and gene set enrichment analyses of collected data will elucidate
new cellular pathways regulated by DIS3 and DIS3L1 and/or by their targets, as well as how
they can be involved in CRC. In addition, this analysis may reveal novel functional networks
through which the RNA exosome modulates the eukaryotic transcriptome.
Description
Keywords
Genómica Funcional e Estrutural Expressão génica