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Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration
- Source :
- Cell Res
- Publication Year :
- 2020
- Publisher :
- Springer Singapore, 2020.
-
Abstract
- Mitotic inheritance of the DNA methylome is a challenging task for the maintenance of cell identity. Whether DNA methylation pattern in different genomic contexts can all be faithfully maintained is an open question. A replication-coupled DNA methylation maintenance model was proposed decades ago, but some observations suggest that a replication-uncoupled maintenance mechanism exists. However, the capacity and the underlying molecular events of replication-uncoupled maintenance are unclear. By measuring maintenance kinetics at the single-molecule level and assessing mutant cells with perturbation of various mechanisms, we found that the kinetics of replication-coupled maintenance are governed by the UHRF1–Ligase 1 and PCNA–DNMT1 interactions, whereas nucleosome occupancy and the interaction between UHRF1 and methylated H3K9 specifically regulate replication-uncoupled maintenance. Surprisingly, replication-uncoupled maintenance is sufficiently robust to largely restore the methylome when replication-coupled maintenance is severely impaired. However, solo-WCGW sites and other CpG sites displaying aging- and cancer-associated hypomethylation exhibit low maintenance efficiency, suggesting that although quite robust, mitotic inheritance of methylation is imperfect and that this imperfection may contribute to selective hypomethylation during aging and tumorigenesis.
- Subjects :
- DNA (Cytosine-5-)-Methyltransferase 1
DNA Replication
Aging
Carcinogenesis
Ubiquitin-Protein Ligases
Inheritance Patterns
Mitosis
Plasma protein binding
Biology
medicine.disease_cause
Genome
Article
Histones
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Protein Domains
Proliferating Cell Nuclear Antigen
medicine
Animals
Humans
Molecular Biology
030304 developmental biology
0303 health sciences
Genome, Human
Lysine
Correction
Mouse Embryonic Stem Cells
Cell Biology
Methylation
DNA Methylation
Cell biology
Nucleosomes
Kinetics
CpG site
chemistry
DNA methylation
CCAAT-Enhancer-Binding Proteins
CpG Islands
030217 neurology & neurosurgery
DNA
HeLa Cells
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell Res
- Accession number :
- edsair.doi.dedup.....5177efc34e72d6adfd08f38c76cffe53