7xib | pdb_00007xib

Cryo-EM structure of human DNMT1 (aa:351-1616) in complex with ubiquitinated H3 and hemimethylated DNA analog (CXXC-disordered form)

Structural highlights

7xib is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.23Å
Ligands:	5CM, EIX, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DNMT1_HUMAN Defects in DNMT1 are the cause of hereditary sensory neuropathy type 1E (HSN1E) [MIM:614116. A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia.^[1]

Function

DNMT1_HUMAN Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.^[2] ^[3] ^[4]

Publication Abstract from PubMed

DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved alpha-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.

Structural basis for activation of DNMT1.,Kikuchi A, Onoda H, Yamaguchi K, Kori S, Matsuzawa S, Chiba Y, Tanimoto S, Yoshimi S, Sato H, Yamagata A, Shirouzu M, Adachi N, Sharif J, Koseki H, Nishiyama A, Nakanishi M, Defossez PA, Arita K Nat Commun. 2022 Nov 21;13(1):7130. doi: 10.1038/s41467-022-34779-4. PMID:36414620^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, B Dyck PJ, Parisi JE, Mer G, Smith DI, Dyck PJ. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011 Jun;43(6):595-600. Epub 2011 May 1. PMID:21532572 doi:10.1038/ng.830
↑ Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431
↑ Pradhan M, Esteve PO, Chin HG, Samaranayke M, Kim GD, Pradhan S. CXXC domain of human DNMT1 is essential for enzymatic activity. Biochemistry. 2008 Sep 23;47(38):10000-9. doi: 10.1021/bi8011725. Epub 2008 Aug, 29. PMID:18754681 doi:10.1021/bi8011725
↑ Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, Bradbury CM, Yu W, Cui H, Lee S, Trepel JB, Feinberg AP, Gius D. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Res. 2008 Apr 15;68(8):2726-35. PMID:18413740 doi:68/8/2726
↑ Kikuchi A, Onoda H, Yamaguchi K, Kori S, Matsuzawa S, Chiba Y, Tanimoto S, Yoshimi S, Sato H, Yamagata A, Shirouzu M, Adachi N, Sharif J, Koseki H, Nishiyama A, Nakanishi M, Defossez PA, Arita K. Structural basis for activation of DNMT1. Nat Commun. 2022 Nov 21;13(1):7130. PMID:36414620 doi:10.1038/s41467-022-34779-4

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, B Dyck PJ, Parisi JE, Mer G, Smith DI, Dyck PJ. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011 Jun;43(6):595-600. Epub 2011 May 1. PMID:21532572 doi:10.1038/ng.830

[2] Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431

[3] Pradhan M, Esteve PO, Chin HG, Samaranayke M, Kim GD, Pradhan S. CXXC domain of human DNMT1 is essential for enzymatic activity. Biochemistry. 2008 Sep 23;47(38):10000-9. doi: 10.1021/bi8011725. Epub 2008 Aug, 29. PMID:18754681 doi:10.1021/bi8011725

[4] Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, Bradbury CM, Yu W, Cui H, Lee S, Trepel JB, Feinberg AP, Gius D. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Res. 2008 Apr 15;68(8):2726-35. PMID:18413740 doi:68/8/2726

[5] Kikuchi A, Onoda H, Yamaguchi K, Kori S, Matsuzawa S, Chiba Y, Tanimoto S, Yoshimi S, Sato H, Yamagata A, Shirouzu M, Adachi N, Sharif J, Koseki H, Nishiyama A, Nakanishi M, Defossez PA, Arita K. Structural basis for activation of DNMT1. Nat Commun. 2022 Nov 21;13(1):7130. PMID:36414620 doi:10.1038/s41467-022-34779-4

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7xib | pdb_00007xib

Cryo-EM structure of human DNMT1 (aa:351-1616) in complex with ubiquitinated H3 and hemimethylated DNA analog (CXXC-disordered form)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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