Isoform Switching Regulates the Response to Ionizing Radiation Through SRSF1.
Majd Abdulghani1, Niema B Razavian2, Joshua T Burdick2
1Rhodes Trust and; Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, United Kingdom.
Summary
Isoform switching significantly impacts cellular responses to ionizing radiation (IR). The study identifies serine/arginine-rich splicing factor 1 (SRSF1) as a key mediator that influences radiosensitivity, offering potential for cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Alternative splicing generates diverse protein isoforms from a single gene.
- Understanding how cells respond to DNA damage, like ionizing radiation (IR), is crucial for cancer therapy.
- Isoform switching's role in radiation response remains understudied.
Purpose of the Study:
- To investigate the impact of isoform switching on cellular responses to ionizing radiation (IR).
- To identify changes in transcript isoform expression following IR exposure.
- To pinpoint proteins mediating these changes and their effect on radiosensitivity.
Main Methods:
- RNA sequencing of B-cell lines from healthy individuals.
- Quantification of alternative splicing using the mixture of isoforms algorithm.
- RNA immunoprecipitation to identify RNA binding protein motifs and validate SRSF1.
- RNA interference and analysis of public cancer patient data to assess SRSF1's role in radiosensitivity.
Main Results:
- Identified approximately 1900 radiation-responsive alternatively spliced isoforms, many with altered gene expression.
- Discovered that IR-responsive isoforms are often shorter, lacking apoptosis/cell division domains but retaining DNA repair domains.
- Identified serine/arginine-rich splicing factor 1 (SRSF1) as a key mediator of radiation-induced isoform switching that promotes apoptosis.
- Demonstrated that decreased SRSF1 expression enhances radiosensitivity in vitro and in cancer patients.
Conclusions:
- Isoform switching plays a critical role in the cellular response to ionizing radiation.
- SRSF1 is a significant mediator of radiation-induced isoform switching.
- SRSF1 shows promise as a biomarker for predicting radiation therapy effectiveness.
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