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The distribution of sense and antisense strand DNA mutations on transcribed duplex DNA contributes to the development of immune and neural systems along with the progression of cancer. Because developmentally matured B cells undergo biologically programmed strand-specific DNA mutagenesis at focal DNA/RNA hybrid structures, they make a convenient system to investigate strand-specific mutagenesis mechanisms. We demonstrate that the sense and antisense strand DNA mutagenesis at the immunoglobulin heavy chain locus and some other regions of the B cell genome depends upon localized RNA processing protein complex formation in the nucleus. Both the physical proximity and coupled activities of RNA helicase Mtr4 (and senataxin) with the noncoding RNA processing function of RNA exosome determine the strand-specific distribution of DNA mutations. Our study suggests that strand-specific DNA mutagenesis-associated mechanisms will play major roles in other undiscovered aspects of organismic development. Copyright © 2017 Elsevier Inc. All rights reserved.


Junghyun Lim, Pankaj Kumar Giri, David Kazadi, Brice Laffleur, Wanwei Zhang, Veronika Grinstein, Evangelos Pefanis, Lewis M Brown, Erik Ladewig, Ophélie Martin, Yuling Chen, Raul Rabadan, François Boyer, Gerson Rothschild, Michel Cogné, Eric Pinaud, Haiteng Deng, Uttiya Basu. Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry. Cell. 2017 Apr 20;169(3):523-537.e15

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PMID: 28431250

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