4.7 Article

Mechanistic insights into recognition of symmetric methylated cytosines in CpG and non-CpG DNA by UHRF1 SRA

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出版社

ELSEVIER
DOI: 10.1016/j.ijbiomac.2020.12.149

关键词

Metadynamics; Non-CpG DNA methylation; UHRF1

资金

  1. Department of Biotechnology (DBT)
  2. Science and Engineering Research Board, Department of Science and Technology, Government of India
  3. Ministry of Human Resource Development, Government of India
  4. University Grants Commission, Government of India

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UHRF1 SRA can recognize non-mCpG DNA, with contrasting mechanisms for hemi-mCpG and fully-mCpHpG DNA recognition. While the binding affinity for fully-mCpG is weaker, UHRF1 SRA exhibits higher affinity for fully-mCpHpG.
Non-CpG DNA methylation (non-mCpG) is enriched in the genome of brain neurons and germline cells in mammals. Accumulation of non-mCpG during postnatal brain development correlates with gene regulation and inactivation of distal regulatory elements. Recently, UHRF1 has been found to contribute to de novo non-CpG methylation, however, whether UHRF1 could recognize non-mCpG is unknown. Here, we have demonstrated through calorimetric measurements that the UHRF1 SRA can recognize mCpH and fully-mCpHpG, types of non-mCpG. Our ITC binding studies endorse the preferential reading of hemi-mCpG by UHRF1 SRA and also show 6-fold weaker binding for fully-mCpG than hemi-mCpG. Despite presence of symmetrical (5-methyl cytosine) 5mCs, stoichiometry of 1:1 for UHRF1 SRA binding to fully-mCpG indicates that UHRF1 SRA may not form a stable complex with fully-mCpG DNA. Contrarily, UHRF1 SRA recognizes fully-mCpHpG with a sloichiomeny of 2:1 protein to DNA duplex with binding affinity higher than fully-mCpG. Our crystal structure of UHRF1 SRA bound to fully-mCpHpG DNA reveals dual flip-out mechanism of 5mC recognition. Metadynamics studies corroborates with ITC data that UHRF1 SRA could not form a stable complex with fully-mCpG DNA. Altogether, this study demonstrates that UHRF1 SRA recognizes non-mCpG DNA and exhibits contrasting mechanisms for hemi-mCpG and fully-mCpHpG DNA recognition. (C) 2020 Elsevier B.V. All rights reserved.

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