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Decoding the MYC locus reveals a druggable ultraconserved RNA element.

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Most essential base pairs in the human MYC gene are noncoding. A 3' untranslated region RNA element is vital for MYC-driven cancers and a potential therapeutic target.

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Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Biology

Background:

  • The human genome contains many noncoding sequences with unknown functions.
  • Understanding the distribution of genetic information between coding and noncoding regions is crucial.

Purpose of the Study:

  • To map the functional landscape of the human MYC locus at base-pair resolution.
  • To identify essential noncoding elements and their role in MYC-driven cancers.

Main Methods:

  • CRISPR saturation mutagenesis with SpRY-Cas9.
  • Functional fitness landscape mapping of the MYC locus.
  • Antisense oligonucleotide targeting of a specific RNA element.

Main Results:

  • 67% of functionally essential base pairs in the MYC locus are noncoding.
  • Noncoding elements' phenotypic impact inversely correlates with evolutionary conservation.
  • An ultraconserved 3' UTR RNA element is essential for MYC-dependent cancer cells.
  • Targeting this RNA element selectively eliminates cancer cells by suppressing MYC function.

Conclusions:

  • Noncoding sequences carry significant functional genetic information.
  • A comprehensive fitness map of the MYC locus was generated.
  • A therapeutically actionable RNA element targeting MYC-driven cancer was identified.