FUBP1 as a Long Tail Driver and Widespread Regulator of Tumor Suppressor Gene Alternative Splicing
Elman, Jessica.
2019
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Comprehensive sequencing approaches have allowed for the
identification of the most frequent contributors to cancer, known as drivers.
These approaches have also revealed a class of somatic mutations in understudied,
infrequently altered genes, referred to as "long tail" (LT) drivers. A key
challenge has been to find clinically relevant LT drivers and understand how they
cooperate to drive ... read moredisease. Here, I identified Far Upstream Binding Protein 1
(FUBP1) as a LT cooperating driver using an in vivo CRISPR screen. FUBP1 loss
cooperates with well-established tumor suppressor genes including PTEN to
transform human mammary epithelial cells by disrupting cellular proliferation,
differentiation and tissue architecture. Mechanistically, FUBP1 is part of the m6A
RNA modification machinery whose loss leads to global changes in RNA splicing and
widespread expression of attenuated tumor suppressors. Components of the FUBP1
protein complex are mutated in human breast cancer, suggesting that its disruption
is a mechanistic driver of breast cancer pathogenesis. These findings suggest that
somatic alteration of a single gene involved in RNA alternative splicing and m6A
methylation can produce the necessary panoply of contributors for neoplastic
transformation.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Charlotte Kuperwasser.
Committee: Philip Hinds, Karl Munger, and Michaela Reagan.
Keywords: Biology, Molecular biology, and Genetics.read less - ID:
- 6395wm67m
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