title: U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation.
abstract: Recurrent mutations in the splicing factor U2AF35 are found in several cancers and myelodysplastic syndrome (MDS). How oncogenic U2AF35 mutants promote transformation remains to be determined. Here we derive cell lines transformed by the oncogenic U2AF35(S34F) mutant and identify aberrantly processed pre-mRNAs by deep sequencing. We find that in U2AF35(S34F)-transformed cells the autophagy-related factor 7 (Atg7) pre-mRNA is abnormally processed, which unexpectedly is not due to altered splicing but rather selection of a distal cleavage and polyadenylation (CP) site. This longer Atg7 mRNA is translated inefficiently, leading to decreased ATG7 levels and an autophagy defect that predisposes cells to secondary mutations, resulting in transformation. MDS and acute myeloid leukemia patient samples harboring U2AF35(S34F) have a similar increased use of the ATG7 distal CP site, and previous studies have shown that mice with hematopoietic cells lacking Atg7 develop an MDS-like syndrome. Collectively, our results reveal a basis for U2AF35(S34F) oncogenic activity.
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sung Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ou
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Chamberlain
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Tessa M
authors.initials: TM
authors.lastname: Simone
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Ching-Man
authors.initials: CM
authors.lastname: Virbasius
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA.
authors.forename: Abdullah M
authors.initials: AM
authors.lastname: Ali
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Programs in Molecular Medicine and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lihua Julie
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA. Electronic address: azra.raza@columbia.edu.
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: michael.green@umassmed.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7 / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D026723:Polyadenylation; D026721:RNA 3' End Processing; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D000072668:Splicing Factor U2AF / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C502661:Atg7 protein, mouse; D012322:RNA Precursors; D012333:RNA, Messenger; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C000607495:Zrsr1 protein, mouse; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7