RNA binding proteins in myelodysplastic syndromes
Liang, Outi (2023)
Liang, Outi
2023
Bioteknologian ja biolääketieteen tekniikan kandidaattiohjelma - Bachelor's Programme in Biotechnology and Biomedical Engineering
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
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Hyväksymispäivämäärä
2023-05-15
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202304274785
https://urn.fi/URN:NBN:fi:tuni-202304274785
Tiivistelmä
A heterogenous group of myeloid neoplasms, which have a risk in turning into acute myeloid leukemia, are called Myelodysplastic syndromes (MDS). The disease can appear at any age, but it is most common in over 70-year-olds. Ineffective hematopoiesis, peripheral cytopenias, and frequent karyotypic abnormalities are typical for the disease.
In MDS there are four commonly mutated splicing factor genes. These genes are SF3B1, U2AF1, SRSF2 and ZRSR2, and they encode splicing factor proteins that function alongside with the spliceosome in premature messenger RNA (pre-mRNA) splicing. Altered splicing patterns are caused by mutated SF3B1, U2AF1, SRSF2 and ZRSR2, and each mutated protein has its characteristics splicing patterns. It is known that splicing machinery gene mutations can predict the outcome of the disease.
Mutations in the gene SF3B1 induce altered branch point sequence recognition, which induces changes in 3’ splice site (SS) recognition. This leads to splicing alterations, such as use of cryptic 3’ SS, intron retention and use of differential cassette exons. SRSF2 mutations favor C- rich sequence recognition and decreased affinity for G-rich sequences, which leads to altered efficiency of exon inclusion. Also, partly increased intron retention has been detected in SRSF2 mutations. U2AF1 and U2AF2 form a heterodimer together and it is involved in 3′ SS selection. Therefore, mutations in U2AF1 causes altered U2AF-RNA binding and recognition of 3’ SS, which leads to altered pre-mRNA splicing. ZRSR2 is a component of small spliceosome that normally removes U12 introns from pre-mRNA. However, mutations in ZRSR2 cause inefficient splicing and can result in U12-type introns retention.
These mutations in genes encoding spliceosomal components can be recognized in over 50% of MDS cases, thus, the splicing machinery is a potential treatment target in treating MDS. There are new approaches in RNA targeting tools that either aim at targeting specific alternative splicing events or splicing factors. Also, mRNA vaccines are studied for cancer treatment.
This thesis focuses on the four splicing machinery gene mutations, where are the mutation hotspots, how the mutation affects the splicing and how this leads to the disease. Also, future potential treatment methods are considered.
In MDS there are four commonly mutated splicing factor genes. These genes are SF3B1, U2AF1, SRSF2 and ZRSR2, and they encode splicing factor proteins that function alongside with the spliceosome in premature messenger RNA (pre-mRNA) splicing. Altered splicing patterns are caused by mutated SF3B1, U2AF1, SRSF2 and ZRSR2, and each mutated protein has its characteristics splicing patterns. It is known that splicing machinery gene mutations can predict the outcome of the disease.
Mutations in the gene SF3B1 induce altered branch point sequence recognition, which induces changes in 3’ splice site (SS) recognition. This leads to splicing alterations, such as use of cryptic 3’ SS, intron retention and use of differential cassette exons. SRSF2 mutations favor C- rich sequence recognition and decreased affinity for G-rich sequences, which leads to altered efficiency of exon inclusion. Also, partly increased intron retention has been detected in SRSF2 mutations. U2AF1 and U2AF2 form a heterodimer together and it is involved in 3′ SS selection. Therefore, mutations in U2AF1 causes altered U2AF-RNA binding and recognition of 3’ SS, which leads to altered pre-mRNA splicing. ZRSR2 is a component of small spliceosome that normally removes U12 introns from pre-mRNA. However, mutations in ZRSR2 cause inefficient splicing and can result in U12-type introns retention.
These mutations in genes encoding spliceosomal components can be recognized in over 50% of MDS cases, thus, the splicing machinery is a potential treatment target in treating MDS. There are new approaches in RNA targeting tools that either aim at targeting specific alternative splicing events or splicing factors. Also, mRNA vaccines are studied for cancer treatment.
This thesis focuses on the four splicing machinery gene mutations, where are the mutation hotspots, how the mutation affects the splicing and how this leads to the disease. Also, future potential treatment methods are considered.
Kokoelmat
- Kandidaatintutkielmat [8798]