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Cited by 59Genomics and Chromatin DynamicsCancer-related Molecular PathwaysChromatin Remodeling and Cancer

Sequence-specific DNA binding by MYC/MAX to low-affinity non-E-box motifs

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Allevato, Michael, Bolotin, Eugene, Grossman, Mark, Mane-Padros, Daniel, Sladek, Frances M., Martinez, Ernest·2017·PLOS ONE
DOI 10.1371/journal.pone.0180147PMC PMC5515408
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Abstract

The MYC oncoprotein regulates transcription of a large fraction of the genome as an obligatory heterodimer with the transcription factor MAX. The MYC:MAX heterodimer and MAX:MAX homodimer (hereafter MYC/MAX) bind Enhancer box (E-box) DNA elements (CANNTG) and have the greatest affinity for the canonical MYC E-box (CME) CACGTG. However, MYC:MAX also recognizes E-box variants and was reported to bind DNA in a "non-specific" fashion in vitro and in vivo. Here, in order to identify potential additional non-canonical binding sites for MYC/MAX, we employed high throughput in vitro protein-binding microarrays, along with electrophoretic mobility-shift assays and bioinformatic analyses of MYC-bound genomic loci in vivo. We identified all hexameric motifs preferentially bound by MYC/MAX in vitro, which include the low-affinity non-E-box sequence AACGTT, and found that the vast majority (87%) of MYC-bound genomic sites in a human B cell line contain at least one of the top 21 motifs bound by MYC:MAX in vitro. We further show that high MYC/MAX concentrations are needed for specific binding to the low-affinity sequence AACGTT in vitro and that elevated MYC levels in vivo more markedly increase the occupancy of AACGTT sites relative to CME sites, especially at distal intergenic and intragenic loci. Hence, MYC binds diverse DNA motifs with a broad range of affinities in a sequence-specific and dose-dependent manner, suggesting that MYC overexpression has more selective effects on the tumor transcriptome than previously thought.

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  • MAX has many weaker and longer-range sequence determinants of binding.

    “with many weaker and longer-range sequence determinants of binding (Allevato et al., 2017).”

    From WILDS: A Benchmark of in-the-Wild Distribution Shifts (2020) · cites this paper as Allevato et al., 2017

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Authors
Allevato, M., Bolotin, E., Grossman, M., Mane-Padros, D., Sladek, F. M., & Martinez, E.
Affiliations
University of California, Riverside (US)
Corresponding author
  • Sladek, Frances M.
  • Martinez, Ernest
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2017-07-18
Volume
12
Issue
7
Pages
e0180147
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0180147
PMC
PMC5515408
OpenAlex
W2737747761
Cited by
59
References
3
Citations by year
2026: 5 · 2025: 10 · 2024: 6 · 2023: 12 · 2022: 5 · 2021: 9 · 2020: 7 · 2019: 3 · 2018: 2
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Cancer Institute (R01CA158540)
  • National Institute of General Medical Sciences (T34GM062756)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK094707)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
c-Myc, Max, Myc-Max heterodimer, E-box, sequence-specific DNA binding, transcription factor binding sites, protein-DNA binding affinity, B-cell lines, dose-dependent binding, tumor transcriptome
MeSH terms
Base Sequence, DNA, Gene Expression Regulation, Humans, Protein Binding, Substrate Specificity, Proto-Oncogene Proteins c-myc, Genomics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Protein Multimerization, Nucleotide Motifs

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