[PDF][PDF] Cancer-associated SF3B1 hotspot mutations induce cryptic 3′ splice site selection through use of a different branch point

RB Darman, M Seiler, AA Agrawal, KH Lim, S Peng… - Cell reports, 2015 - cell.com
RB Darman, M Seiler, AA Agrawal, KH Lim, S Peng, D Aird, SL Bailey, EB Bhavsar, B Chan…
Cell reports, 2015cell.com
Recurrent mutations in the spliceosome are observed in several human cancers, but their
functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated
component of the spliceosome in cancer, is involved in the recognition of the branch point
sequence (BPS) during selection of the 3′ splice site (ss) in RNA splicing. Here, we report
that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and
establish aberrant 3′ ss selection as the most frequent splicing defect. Strikingly, mutant …
Summary
Recurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3′ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3′ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3′ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.
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