Details

Autor(en) / Beteiligte

• Burke, Evan J.
• Rodda, Samuel S.
• Lund, Sean R.
• Sun, Zhiyi
• Zeroka, Malcolm R.
• O’Toole, Katherine H.
• Parker, Mackenzie J.
• Doshi, Dharit S.
• Guan, Chudi
• Lee, Yan-Jiun
• Dai, Nan
• Hough, David M.
• Shnider, Daria A.
• Corrêa, Ivan R.
• Weigele, Peter R.
• Saleh, Lana

Titel

Phage-encoded ten-eleven translocation dioxygenase (TET) is active in C5-cytosine hypermodification in DNA

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2021-06, Vol.118 (26)

Ort / Verlag

Washington: National Academy of Sciences

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Significance Chemical tailoring of canonical bases expands the functionality of DNA in the same manner that posttranscriptional and -translational modifications enhance functional diversity in RNA and proteins. We describe the activities of ten-eleven translocation dioxygenase (TET)-like iron(II)- and 2-oxo-glutarate–dependent 5mC dioxygenases that are encoded by several bacteriophages to enable hypermodification of C5-methyl cytosine bases in their DNA. Phage TETs act on methylation marks deposited within GpC sequences by functionally-associated cytosine 5-methyltransferases. The hydroxymethyl groups installed are further elaborated by tailoring enzymes, thereby decorating the phage DNA with diverse, complex modifications. These modifications are predicted to have protective roles against host defenses during viral infection. TET/JBP (ten-eleven translocation/base J binding protein) enzymes are iron(II)- and 2-oxo-glutarate–dependent dioxygenases that are found in all kingdoms of life and oxidize 5-methylpyrimidines on the polynucleotide level. Despite their prevalence, few examples have been biochemically characterized. Among those studied are the metazoan TET enzymes that oxidize 5-methylcytosine in DNA to hydroxy, formyl, and carboxy forms and the euglenozoa JBP dioxygenases that oxidize thymine in the first step of base J biosynthesis. Both enzymes have roles in epigenetic regulation. It has been hypothesized that all TET/JBPs have their ancestral origins in bacteriophages, but only eukaryotic orthologs have been described. Here we demonstrate the 5mC-dioxygenase activity of several phage TETs encoded within viral metagenomes. The clustering of these TETs in a phylogenetic tree correlates with the sequence specificity of their genomically cooccurring cytosine C5-methyltransferases, which install the methyl groups upon which TETs operate. The phage TETs favor Gp5mC dinucleotides over the 5mCpG sites targeted by the eukaryotic TETs and are found within gene clusters specifying complex cytosine modifications that may be important for DNA packaging and evasion of host restriction.