The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index.
Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island
Open accessAbstract
Chronic exposure to inducers of DNA base oxidation and single and double strand breaks contribute to tumorigenesis. In addition to the genetic changes caused by this DNA damage, such tumors often contain epigenetically silenced genes with aberrant promoter region CpG island DNA hypermethylation. We herein explore the relationships between such DNA damage and epigenetic gene silencing using an experimental model in which we induce a defined double strand break in an exogenous promoter construct of the E-cadherin CpG island, which is frequently aberrantly DNA hypermethylated in epithelial cancers. Following the onset of repair of the break, we observe recruitment to the site of damage of key proteins involved in establishing and maintaining transcriptional repression, namely SIRT1, EZH2, DNMT1, and DNMT3B, and the appearance of the silencing histone modifications, hypoacetyl H4K16, H3K9me2 and me3, and H3K27me3. Although in most cells selected after the break, DNA repair occurs faithfully with preservation of activity of the promoter, a small percentage of the plated cells demonstrate induction of heritable silencing. The chromatin around the break site in such a silent clone is enriched for most of the above silent chromatin proteins and histone marks, and the region harbors the appearance of increasing DNA methylation in the CpG island of the promoter. During the acute break, SIRT1 appears to be required for the transient recruitment of DNMT3B and subsequent methylation of the promoter in the silent clones. Taken together, our data suggest that normal repair of a DNA break can occasionally cause heritable silencing of a CpG island-containing promoter by recruitment of proteins involved in silencing. Furthermore, with contribution of the stress-related protein SIRT1, the break can lead to the onset of aberrant CpG island DNA methylation, which is frequently associated with tight gene silencing in cancer.
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“Recent studies have shown that DNA damage can induce changes in gene expression and histone modification patterns that may be mediated, in part, by the conserved lifespan regulatory gene SIRT1 (see below), suggesting a possible mechanistic link between DNA damage, epigenomic state and ageing (45,46).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [46]
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1 retracted
RETRACTED: DNA Damage, Homology-Directed Repair, and DNA Methylation
Cuozzo, C., Porcellini, A., Angrisano, T., Morano, A., Lee, B., Pardo, A. D., Messina, S., Iuliano, R., Fusco, A., Santillo, M. R., et al. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030110 · Cited by 198
RetractedJenuwein, T., & Allis, C. D. (2001) · Science · doi:10.1126/science.1063127 · Cited by 9,756
The language of covalent histone modifications
Strahl, B. D., & Allis, C. D. (2000) · Nature · doi:10.1038/47412 · Cited by 8,679
Okano, M., Bell, D. W., Haber, D. A., & Li, E. (1999) · Cell · doi:10.1016/s0092-8674(00)81656-6 · Cited by 6,143
Chen, X., Xiu, M., Xing, J., Yu, S., Min, D., & Guo, F. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479439 · Cited by 5,760
Genome maintenance mechanisms for preventing cancer
Hoeijmakers, J. H. J. (2001) · Nature · doi:10.1038/35077232 · Cited by 3,939
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510
Histone deacetylases (HDACs): characterization of the classical HDAC family
RUIJTER, A. J. M. D., GENNIP, A. H. V., CARON, H. N., KEMP, S., & KUILENBURG, A. B. P. V. (2003) · Biochemical Journal · doi:10.1042/bj20021321 · Cited by 3,114
hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S., Frye, R. A., Pandita, T. K., Guarente, L., & Weinberg, R. A. (2001) · Cell · doi:10.1016/s0092-8674(01)00527-x · Cited by 2,690
Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo
Rogakou, E. P., Boon, C., Redon, C., & Bonner, W. M. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.5.905 · Cited by 2,422
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Self-citationNeural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323
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Metadata
- Authors
- O'Hagan, H. M., Mohammad, H. P., & Baylin, S. B.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Baylin, Stephen B.
- ORCID
- Baylin, Stephen B.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-08-15
- Volume
- 4
- Issue
- 8
- Pages
- e1000155
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2491723
- OpenAlex
- W2092761963
- Cited by
- 386
- References
- 86
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 11 · 2023: 22 · 2022: 14 · 2021: 23 · 2020: 21 · 2019: 20 · 2018: 26 · 2017: 23 · 2016: 24 · 2015: 23 · 2014: 23 · 2013: 32 · 2012: 26
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA043318, CA 043318)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- 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
- Keywords
- DNA double-strand breaks, DNA damage, epigenetic silencing, SIRT1, DNA methylation, CpG island hypermethylation, E-cadherin promoter, DNA repair, DNMT3B, DNMT1, EZH2, histone modifications, H3K9me3, H3K27me3, transcriptional repression, cancer epigenetics
- MeSH terms
- DNA Methyltransferase 3B, Chromatin, DNA (Cytosine-5-)-Methyltransferases, Humans, Promoter Regions, Genetic, CpG Islands, DNA Methylation, Gene Silencing, Sirtuins, Cell Line, Tumor, DNA Breaks, Double-Stranded, Sirtuin 1
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