Quaternary structure and regulation of mammalian DNA methyltransferase 3a (Dnmt3a)

  • The Dnmt3 family includes two catalytically active de novo methyltransferases (Dnmt3a and Dnmt3b) and one catalytically inactive regulatory factor called Dnmt3L. The N-terminal part of Dnmt3a consists of an ADD and a PWWP domain, we have shown that the ADD domain interacts with H3K4 unmethylated tails and the PWWP domain interacts with H3K36me3 marks. These interactions are responsible for the regulation of Dnmt3a's activity as well as for targeting to heterochromatin. We have identified that Dnmt3a and Dnmt3L form a heterotetramer that methylates two CpG sites on opposite DNA strands in a distance of 8-10 bps. We have shown that Dnmt3a forms a linear multimer and it binds to many DNA molecules oriented in parallel. This process is required for the heterochromatic localization of Dnmt3a in cells. The regulator protein Dnmt3L reorganizes the quaternary structures of Dnmt3a, thereby prevents multimerization. In addition to formation of protein multimers, Dnmt3a complexes bind cooperatively to DNA forming protein-DNA filaments. This might be required for generation of 8-10 bp periodicity patterns at imprinted genes and tight packing of Dnmt3a at the heterochromatic region. In addition, we have identified that the enzymatic activity Dnmt3a is regulated by phosphorylation. Casein kinase 2 mediated phosphorylation of the Dnmt3a negatively regulates its enzymatic activity in cells. Adding to existing evidence, our data uncovered novel mechanism of regulation of Dnmt3a activity, which are required for the proper DNA methylation patterns in cells. Also, using a newly developed high throughput assay, we have identified novel inhibitors to Dnmt3a from chemical libraries and identified new compounds purified from the dietary black tea and coffee polyphenols, which inhibit the Dnmt3a activity moderately.

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Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Author:Arumugam Rajavelu
Referee:Albert Jeltsch, Neil Brockdorff, Klaudia Brix
Advisor:Albert Jeltsch
Persistent Identifier (URN):urn:nbn:de:101:1-201307119475
Document Type:PhD Thesis
Language:English
Date of Successful Oral Defense:2011/10/04
Date of First Publication:2011/11/10
Full Text Embargo Until:2012/12/31
PhD Degree:Biochemistry
School:SES School of Engineering and Science
Library of Congress Classification:Q Science / QD Chemistry / QD241-441 Organic chemistry / QD415-436 Biochemistry / QD431 Proteins, peptides, amino acids, etc.
Call No:Thesis 2011/36

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