Structure of DNMT1-DNA Complex Reveals a Role for Autoinhibition in Maintenance DNA Methylation

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Science (Washington, D.C.)

DOI:https://doi.org/10.1126/science.1195380· OSTI ID:1041969

Song, J; Rechkoblit, O; Bestor, T; Patel, D

Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1). We have solved structures of mouse and human DNMT1 composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation. In addition, a loop projecting from BAH2 interacts with the target recognition domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted position and preventing it from inserting into the DNA major groove. Our studies identify an autoinhibitory mechanism, in which unmethylated CpG dinucleotides are occluded from the active site to ensure that only hemimethylated CpG dinucleotides undergo methylation.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041969
• Report Number(s): BNL--97647-2012-JA
• Journal Information: Science (Washington, D.C.), Journal Name: Science (Washington, D.C.) Journal Issue: 6020 Vol. 331; ISSN SCIEAS; ISSN 0036-8075
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
DNA
MAINTENANCE
METHYLATION
TARGETS