Seminar: John Prensner, MD, PhD

“Translating the cancer genome: dark matter proteins”
John Prensner, M.D., Ph.D.

Physician, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Instructor of Pediatrics, Harvard Medical School

Co-Hosts: The Center for RNA Biomedicine, Department of Computational Medicine & Bioinformatics, and Department of Pediatric Oncology

Hybrid Seminar:
In-person: Biomedical Science Research Building (BSRB), ABC Seminar rooms
Zoom: https://umich.zoom.us/webinar/register/WN_bC6oy6VZTLy3ke4iMS2sKQ

Keywords: cancer, ribosome profiling, functional genomics, gene discovery

Abstract: Although genomic analyses predict many non-canonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins in diseases such as cancer. Here, we have developed functional genomics platforms to systematically interrogate non-canonical ORFs identified in ribosome profiling data. Using CRISPR loss-of-function screens in numerous human cancer models, we define the frequency with which ORFs contribute to cell essentiality phenotypes. We further constructed large-scale ORF plasmid libraries to assess their capacity to encode a protein and induce cancer cell transcriptional changes. We pursued focused investigation of several uncharacterized protein-coding loci, defining roles for the lncRNA-ORF GREP1 in breast cancer and the ASNSD1 upstream ORF (uORF) in medulloblastoma. Lastly, we have assembled a pathway to bring such ORF candidates into the mainstream of biological research via an international consortium of gene database stakeholders. Together, this work establishes non-canonical ORFs as critical mediators of cancer cell biology, suggests their potential promise as therapeutic targets in cancer, and outlines a path forward for dissemination of these ORFs amongst the global research community.

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