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Noncanonical open reading frames encode functional proteins essential for cancer cell survival.
Prensner, John R; Enache, Oana M; Luria, Victor; Krug, Karsten; Clauser, Karl R; Dempster, Joshua M; Karger, Amir; Wang, Li; Stumbraite, Karolina; Wang, Vickie M; Botta, Ginevra; Lyons, Nicholas J; Goodale, Amy; Kalani, Zohra; Fritchman, Briana; Brown, Adam; Alan, Douglas; Green, Thomas; Yang, Xiaoping; Jaffe, Jacob D; Roth, Jennifer A; Piccioni, Federica; Kirschner, Marc W; Ji, Zhe; Root, David E; Golub, Todd R.
Afiliação
  • Prensner JR; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Enache OM; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Luria V; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
  • Krug K; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Clauser KR; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • Dempster JM; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Karger A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Wang L; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Stumbraite K; IT-Research Computing, Harvard Medical School, Boston, MA, USA.
  • Wang VM; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Botta G; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Lyons NJ; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Goodale A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Kalani Z; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Fritchman B; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Brown A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Alan D; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Green T; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Yang X; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Jaffe JD; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Roth JA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Piccioni F; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Kirschner MW; Inzen Therapeutics, Cambridge, MA, USA.
  • Ji Z; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Root DE; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Golub TR; Merck Research Laboratories, Boston, MA, USA.
Nat Biotechnol ; 39(6): 697-704, 2021 06.
Article em En | MEDLINE | ID: mdl-33510483
ABSTRACT
Although genomic analyses predict many noncanonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins. Here we experimentally interrogated 553 candidates selected from noncanonical ORF datasets. Of these, 57 induced viability defects when knocked out in human cancer cell lines. Following ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. Clustered regularly interspaced short palindromic repeat (CRISPR) tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We found that one of these ORFs, G029442-renamed glycine-rich extracellular protein-1 (GREP1)-encodes a secreted protein highly expressed in breast cancer, and its knockout in 263 cancer cell lines showed preferential essentiality in breast cancer-derived lines. The secretome of GREP1-expressing cells has an increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth-inhibitory effect of GREP1 knockout. Our experiments suggest that noncanonical ORFs can express biologically active proteins that are potential therapeutic targets.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sobrevivência Celular / Proteínas de Neoplasias / Neoplasias Limite: Humans Idioma: En Revista: Nat Biotechnol Assunto da revista: BIOTECNOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sobrevivência Celular / Proteínas de Neoplasias / Neoplasias Limite: Humans Idioma: En Revista: Nat Biotechnol Assunto da revista: BIOTECNOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos