Document Type
Article
Publication Date
5-16-2024
Original Citation
Benbarche S,
Pineda J,
Galvis L,
Biswas J,
Liu B,
Wang E,
Zhang Q,
Hogg S,
Lyttle K,
Dahi A,
Lewis A,
Sarchi M,
Rahman J,
Fox N,
Ai Y,
Mehta S,
Garippa R,
Ortiz-Pacheco J,
Li Z,
Monetti M,
Stanley R,
Doulatov S,
Bradley R,
Abdel-Wahab O.
GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies. Mol Cell. 2024;84(10):1886-903.e10.
Keywords
JGM, RNA Splicing Factors, Humans, Animals, Phosphoproteins, Mutation, Hematologic Neoplasms, Mice, RNA Splicing, DEAD-box RNA Helicases, Hematopoiesis, HEK293 Cells, Introns, RNA Helicases, RNA-Binding Proteins
JAX Source
Mol Cell. 2024;84(10):1886-903.e10.
ISSN
1097-4164
PMID
38688280
DOI
https://doi.org/10.1016/j.molcel.2024.04.006
Abstract
Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.