Transcription Factors and DNA Repair Enzymes Compete for Damaged Promoter Sites
Open accessAbstract
Transcriptional regulation is a tightly regulated, vital process. The transcription factor cyclic AMP-response element-binding protein 1 (CREB1) controls ∼25% of the mammalian transcriptome by binding the CREB1 binding site consensus sequence (CRE) sequence (TGACGTCA). DNA lesions within CRE modulate CREB1 binding negatively and positively. Because appropriate DNA lesions also interact with base excision repair proteins, we investigated whether CREB1 and repair glycosylases compete with each other. We incubated 39-mer CRE-containing double-stranded oligonucleotides with recombinant CREB1 alone or with UNG2 or OGG1, followed by EMSA. The CpG islet within CRE was modified to contain a G/U or 8-oxoG (°G)/C mispair. OGG1 and CREB1 reversibly competed for CRE containing an °G/C pair. Also, OGG1 blocked CREB1 from dimerizing by 69%, even when total CREB1 binding was reduced only by 20-30%. In contrast, bound CREB1 completely prevented access to G/U-containing CRE by UNG2 and, therefore, to base excision repair, whereas UNG2 exposure prevented CREB1 binding. CREB1 dimerization was unaffected by UNG2 when CREB1 bound to CRE, but was greatly reduced by prior UNG2 exposure. To explore physiological relevance, we microinjected zebrafish embryos with the same oligonucleotides, as a sink for endogenous CREB1. As predicted, microinjection with unmodified or lesion-containing CRE, but not scrambled CRE or scrambled CRE with a G/U mispair, resulted in increased embryo death. However, only the G/U mispair in native CRE resulted in substantial developmental abnormalities, thus confirming the danger of unrepaired G/U mispairs in promoters. In summary, CREB1 and DNA glycosylases compete for damaged CRE in vitro and in vivo, thus blocking DNA repair and resulting in transcriptional misregulation leading to abnormal development.
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8oxoG can repress gene transcription through multiple mechanisms, including blocking transcription factor binding, recruiting chromatin remodelers that methylate gene promoters, and erroneous BER that can result in single nucleotide variations.
“8oxoG is capable of repressing gene transcription through many mechanisms, including blocking transcription factor binding (Ghosh & Mitchell, 1999; Moore et al, 2016), recruiting chromatin remodelers that result in the methylation of gene promoters(Wang et al, 2018b; Xia et al, 2017, 4), and erroneous repair through BER, which could result in single nucleotide variations (SNVs).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Moore et al, 2016
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- Authors
- Moore, S. P. G., Kruchten, J., Toomire, K. J., & Strauss, P. R.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Strauss, Phyllis R.
- ORCID
- Moore, Stephen P.G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 291
- Issue
- 11
- Pages
- 5452-5460
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4786688
- OpenAlex
- W2237137237
- Cited by
- 28
- References
- 40
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 2
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- G. Harold and Leila Y. Mathers Foundation
- Aid for Cancer Research
- Northeastern University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- CREB1, base excision repair, UNG2, OGG1, 8-oxoguanine, CpG islands, transcriptional regulation, zebrafish embryonic development, embryonic lethality
- MeSH terms
- Animals, Base Sequence, DNA Damage, DNA Repair, Humans, Promoter Regions, Genetic, Recombinant Proteins, Zebrafish, Consensus Sequence, Cyclic AMP Response Element-Binding Protein, DNA Glycosylases, Protein Multimerization
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