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Human Molecular Genetics Advance Access published online on March 16, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl059
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 7, 2005
Revised February 8, 2006
Accepted March 9, 2006

Article

Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L

Zheng-Hua Xie 1, Yan-Nv Huang 1, Zhao-Xia Chen 2, Arthur D. Riggs 2, Jian-Ping Ding 3, Humaira Gowher 4, Albert Jeltsch 5, Hiroyuki Sasaki 6, Kenichiro Hata 6, and Guo-Liang Xu 7 *

1 The State Key Laboratory of Molecular Biology, Institute of the City of Hope, Duarte, California 91010, USA
2 Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA
3 the Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
4 Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD, USA
5 The School of Engineering and Science, International University Bremen, Campus Ring 1, 28759 Bremen, Germany
6 Department of Integrated Genetics, Division of Human Genetics, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Japan
7 Institute of Biochemistry and Cell Biology Chinese Academy of Sciences 320 Yueyang Road Shanghai 200031, China

* To whom correspondence should be addressed.
Guo-Liang Xu, E-mail: glxu{at}sibs.ac.cn.


  Abstract

Deficiency in DNA methyltransferase DNMT3B causes a recessive human disorder characterized by immunodeficiency, centromeric instability and facial anomalies (ICF) in association with defects in genomic methylation. The majority of ICF mutations are single amino acid substitutions in the conserved catalytic domain of DNMT3B which are believed to impair its enzymatic activity directly. The establishment of intact genomic methylation patterns in development requires a fine regulation of the de novo methylation activity of the two related methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. Here, we show that two DNMT3B mutant proteins with ICF-causing substitution (A766P and R840Q) displayed a methylation activity similar to the wild-type enzyme both in vitro and in vivo. However, their stimulation by Dnmt3L was severely compromised due to deficient protein interaction. Our findings suggest that methylation defects in ICF syndrome may also result from impaired stimulation of DNMT3B activity by DNMT3L or other unknown regulatory factors as well as from a weakened basal catalytic activity of the mutant DNMT3B protein per se.


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