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rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase required for meiosis and transposon repression in the mouse male germline

Devanshi Jain, Cem Meydan, Julian Lange, Corentin Claeys Bouuaert, Christopher E. Mason, Kathryn V. Anderson, View ORCID ProfileScott Keeney
doi: https://doi.org/10.1101/121822
Devanshi Jain
1Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
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  • For correspondence: jaind@mskcc.org s-keeney@ski.mskcc.org
Cem Meydan
2Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America
3The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America
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Julian Lange
1Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
4Howard Hughes Medical Institute, New York, New York, United States of America
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Corentin Claeys Bouuaert
1Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
4Howard Hughes Medical Institute, New York, New York, United States of America
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Christopher E. Mason
2Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America
3The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America
5The Feil Family Brain and Mind Research Institute, New York, New York, United States of America
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Kathryn V. Anderson
6Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
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Scott Keeney
1Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
4Howard Hughes Medical Institute, New York, New York, United States of America
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  • ORCID record for Scott Keeney
  • For correspondence: jaind@mskcc.org s-keeney@ski.mskcc.org
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Abstract

Transcriptional silencing by heritable cytosine-5 methylation is an ancient strategy to repress transposable elements. It was previously thought that mammals possess four DNA methyltransferase paralogs—Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l—that establish and maintain cytosine-5 methylation. Here we identify a fifth paralog, Dnmt3c, that is essential for retrotransposon methylation and repression in the mouse male germline. From a phenotype-based forward genetics screen, we isolated a mutant mouse called ‘rahu’, which displays severe defects in double-strand-break repair and homologous chromosome synapsis during male meiosis, resulting in sterility. rahu is an allele of a transcription unit (Gm14490, renamed Dnmt3c) that was previously mis-annotated as a Dnmt3-family pseudogene. Dnmt3c encodes a catalytically active cytosine methyltransferase, and rahu mutants harbor a non-synonymous mutation of a conserved residue within one of its cytosine methyltransferase motifs, similar to a mutation in human DNMT3B observed in patients with immunodeficiency, centromeric instability and facial anomalies syndrome. The rahu mutation lies at a potential dimerization interface and near the potential DNA binding interface, but it does not eliminate methyltransferase activity of recombinant protein in vitro, suggesting that it compromises protein-protein and/or protein-DNA interactions required for normal DNMT3C function in vivo. rahu mutant males fail to establish normal methylation within retrotransposon sequences in the germline and accumulate higher levels of transposon-derived transcripts and proteins, particularly from distinct L1 and ERVK retrotransposon families. Phylogenetic analysis indicates that Dnmt3c arose during rodent evolution by tandem duplication of Dnmt3b, after the divergence of the Dipodoidea and Muroidea superfamilies. These findings provide insight into the evolutionary dynamics and functional specialization of the transposon suppression machinery critical for mammalian sexual reproduction.

Author Summary Half our genomes are made up of transposons, mobile elements that pose a constant threat to genome stability. As a defense strategy, genomes methylate transposon sequences, thereby preventing their expression and restraining their mobility. We have generated a mutant mouse, called ‘rahu’, that fails to methylate transposons in germ cells, suffers an increase in transposon expression and, as a result, is sterile. rahu mice carry a mutation in a new gene, Dnmt3c, which appeared during rodent evolution through gene duplication 45–55 million years ago and is an essential component of the germline defense system against transposons in male mice.

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Posted March 29, 2017.
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rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase required for meiosis and transposon repression in the mouse male germline
Devanshi Jain, Cem Meydan, Julian Lange, Corentin Claeys Bouuaert, Christopher E. Mason, Kathryn V. Anderson, Scott Keeney
bioRxiv 121822; doi: https://doi.org/10.1101/121822
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rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase required for meiosis and transposon repression in the mouse male germline
Devanshi Jain, Cem Meydan, Julian Lange, Corentin Claeys Bouuaert, Christopher E. Mason, Kathryn V. Anderson, Scott Keeney
bioRxiv 121822; doi: https://doi.org/10.1101/121822

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