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Translational control of the spliceosome under oncogenic stress

Sejas Martínez, Álvaro (2019) MOBN03 20182
Degree Projects in Molecular Biology
Popular Abstract
Splicing in cancer

Proteins are functional molecules responsible for every biochemical process that sustain living organisms. However, how genetic information is expanded to generate amazing diversity of proteins during development and in cancer remains still mostly unresolved.
The mechanism we have to account for this diversity is known as splicing. Information-containing RNA molecules, copies of the DNA in our genes, are processed during splicing to give the templates for protein production, also called translation. Splicing can then generate different templates which give rise to different proteins with diverse functions from a single gene. Therefore, splicing is under constant control in the cell to guarantee its correct... (More)
Splicing in cancer

Proteins are functional molecules responsible for every biochemical process that sustain living organisms. However, how genetic information is expanded to generate amazing diversity of proteins during development and in cancer remains still mostly unresolved.
The mechanism we have to account for this diversity is known as splicing. Information-containing RNA molecules, copies of the DNA in our genes, are processed during splicing to give the templates for protein production, also called translation. Splicing can then generate different templates which give rise to different proteins with diverse functions from a single gene. Therefore, splicing is under constant control in the cell to guarantee its correct functioning. Not surprisingly, alterations in splicing are common in disease. Cancer, for example, presents incorrect splicing of genes important for the defence against tumours or genes causing cancer generating non-functional or hyper-functional proteins respectively. Looking to understand the reason behind this variation, we focused on the spliceosome, the cellular apparatus that carries out splicing. The spliceosome is formed by more than 200 proteins, also termed splicing factors. Given its diverse protein composition and the fact that protein production is increased in cancer, we proposed that changes in the quantity of some of those proteins could change the composition of the complex and maybe cause the splicing errors observed in cancer.

Key proteins for splicing are actively regulated in cancer
To study this, we imitated the early stages of cancer by expressing cancer-provoking genes in normal human cells. In these cells, we measured the production of the proteins constituting the spliceosome noticing that, as we proposed, some of them were being synthesized more than in normal cells. A group of proteins highly affected was identified as the U2 complex. The role of this complex in the spliceosome is to ensure that splicing occurs appropriately and its incorrect functioning is linked to splicing alterations. After observing the U2 complex regulation in cancer cells, we focused on understanding how it happened. Our analysis of RNA regulatory regions reveal novel selective mechanisms for aberrant function of specific U2 components in cancer cells.

U2 spliceosome as a potential clinical target
All in all, our study helped understand how the spliceosome, the molecular machine in charge of splicing, is altered in the early stages of cancer. We revealed how the U2 complex, integral for correct splicing, is strongly regulated in tumour conditions. Proving the association between changes in the levels of these splicing factors and splicing alterations in cancer, together with our discoveries on how these changes take place, could open new treatment opportunities in the field.


Master’s Degree Project in Molecular Genetics, Biotechnology, Molecular Biology, 60 credits, 2019.

Supervisor: Cristian Bellodi, RNA and Stem Cell Biology, Division of Molecular Hematology, BMC. (Less)
Please use this url to cite or link to this publication:
author
Sejas Martínez, Álvaro
supervisor
organization
course
MOBN03 20182
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8995082
date added to LUP
2019-09-16 14:14:21
date last changed
2019-09-16 14:14:21
@misc{8995082,
  author       = {{Sejas Martínez, Álvaro}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Translational control of the spliceosome under oncogenic stress}},
  year         = {{2019}},
}