Unknown

Dataset Information

0

Structural and biochemical insight into the mechanism of dual CpG site binding and methylation by the DNMT3A DNA methyltransferase.


ABSTRACT: DNMT3A/3L heterotetramers contain two active centers binding CpG sites at 12 bp distance, however their interaction with DNA not containing this feature is unclear. Using randomized substrates, we observed preferential co-methylation of CpG sites with 6, 9 and 12 bp spacing by DNMT3A and DNMT3A/3L. Co-methylation was favored by AT bases between the 12 bp spaced CpG sites consistent with their increased bending flexibility. SFM analyses of DNMT3A/3L complexes bound to CpG sites with 12 bp spacing revealed either single heterotetramers inducing 40° DNA bending as observed in the X-ray structure, or two heterotetramers bound side-by-side to the DNA yielding 80° bending. SFM data of DNMT3A/3L bound to CpG sites spaced by 6 and 9 bp revealed binding of two heterotetramers and 100° DNA bending. Modeling showed that for 6 bp distance between CpG sites, two DNMT3A/3L heterotetramers could bind side-by-side on the DNA similarly as for 12 bp distance, but with each CpG bound by a different heterotetramer. For 9 bp spacing our model invokes a tetramer swap of the bound DNA. These additional DNA interaction modes explain how DNMT3A and DNMT3A/3L overcome their structural preference for CpG sites with 12 bp spacing during the methylation of natural DNA.

SUBMITTER: Emperle M 

PROVIDER: S-EPMC8373138 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structural and biochemical insight into the mechanism of dual CpG site binding and methylation by the DNMT3A DNA methyltransferase.

Emperle Max M   Bangalore Disha M DM   Adam Sabrina S   Kunert Stefan S   Heil Hannah S HS   Heinze Katrin G KG   Bashtrykov Pavel P   Tessmer Ingrid I   Jeltsch Albert A  

Nucleic acids research 20210801 14


DNMT3A/3L heterotetramers contain two active centers binding CpG sites at 12 bp distance, however their interaction with DNA not containing this feature is unclear. Using randomized substrates, we observed preferential co-methylation of CpG sites with 6, 9 and 12 bp spacing by DNMT3A and DNMT3A/3L. Co-methylation was favored by AT bases between the 12 bp spaced CpG sites consistent with their increased bending flexibility. SFM analyses of DNMT3A/3L complexes bound to CpG sites with 12 bp spacing  ...[more]

Similar Datasets

| S-EPMC9530848 | biostudies-literature
| S-EPMC7144912 | biostudies-literature
| S-EPMC3107267 | biostudies-literature
| S-EPMC5389507 | biostudies-literature
| S-EPMC5709737 | biostudies-literature
| S-EPMC139244 | biostudies-literature
| S-EPMC6316889 | biostudies-literature
| S-EPMC5814352 | biostudies-literature
| S-EPMC3064781 | biostudies-literature
| S-EPMC9499004 | biostudies-literature