U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation

Sung Mi Park; Jianhong Ou; Lynn Chamberlain; Tessa M Simone; Huan Yang; Ching-Man Virbasius; Abdullah M Ali; Lihua Julie Zhu; Siddhartha Mukherjee; Azra Raza; Michael R Green

doi:10.1016/j.molcel.2016.04.011

U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation

Mol Cell. 2016 May 19;62(4):479-90. doi: 10.1016/j.molcel.2016.04.011. Epub 2016 May 12.

Authors

Affiliations

¹ 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.
² Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
³ Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA.
⁴ 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.
⁵ 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.
⁶ 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.

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.

MeSH terms

Aged
Aged, 80 and over
Animals
Autophagy
Autophagy-Related Protein 7 / genetics*
Autophagy-Related Protein 7 / metabolism
Cell Line, Transformed
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Mitochondria / metabolism
Mitochondria / pathology
Mutation
Myelodysplastic Syndromes / genetics*
Myelodysplastic Syndromes / metabolism
Myelodysplastic Syndromes / pathology
Polyadenylation
RNA 3' End Processing*
RNA Interference
RNA Precursors / genetics*
RNA Precursors / metabolism
RNA, Messenger / genetics*
RNA, Messenger / metabolism
Splicing Factor U2AF / genetics*
Splicing Factor U2AF / metabolism
Time Factors
Transfection
Tumor Burden

Substances

Atg7 protein, mouse
RNA Precursors
RNA, Messenger
Splicing Factor U2AF
U2AF1 protein, human
Zrsr1 protein, mouse
ATG7 protein, human
Autophagy-Related Protein 7

Abstract

MeSH terms

Substances

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