Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA
Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelat...
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National Academy of Sciences
2012
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| Online Access: | http://hdl.handle.net/1721.1/72533 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0002-4607-5337 |
| _version_ | 1811095712058834944 |
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| author | Pang, Bo McFaline, Jose Luis Burgis, Nicholas E. Taghizadeh, Koli Sullivan, Matthew R. Elmquist, C. Eric Cunningham, Richard P. Dedon, Peter C. Dong, Min, 1968- |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Pang, Bo McFaline, Jose Luis Burgis, Nicholas E. Taghizadeh, Koli Sullivan, Matthew R. Elmquist, C. Eric Cunningham, Richard P. Dedon, Peter C. Dong, Min, 1968- |
| author_sort | Pang, Bo |
| collection | MIT |
| description | Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelated mechanisms, including hydrolysis, nitrosative chemistry, and deaminase enzymes. Here we present a fourth mechanism contributing to the burden of nucleobase deamination: incorporation of hypoxanthine and xanthine into DNA and RNA caused by defects in purine nucleotide metabolism. Using Escherichia coli and Saccharomyces cerevisiae with defined mutations in purine metabolism in conjunction with analytical methods for quantifying deaminated nucleobases in DNA and RNA, we observed large increases (up to 600-fold) in hypoxanthine in both DNA and RNA in cells unable to convert IMP to XMP or AMP (IMP dehydrogenase, guaB; adenylosuccinate synthetase, purA, and ADE12), and unable to remove dITP/ITP and dXTP/XTP from the nucleotide pool (dITP/XTP pyrophosphohydrolase, rdgB and HAM1). Conversely, modest changes in xanthine levels were observed in RNA (but not DNA) from E. coli lacking purA and rdgB and the enzyme converting XMP to GMP (GMP synthetase, guaA). These observations suggest that disturbances in purine metabolism caused by known genetic polymorphisms could increase the burden of mutagenic deaminated nucleobases in DNA and interfere with gene expression and RNA function, a situation possibly exacerbated by the nitrosative stress of concurrent inflammation. The results also suggest a mechanistic basis for the pathophysiology of human inborn errors of purine nucleotide metabolism. |
| first_indexed | 2024-09-23T16:25:43Z |
| format | Article |
| id | mit-1721.1/72533 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:25:43Z |
| publishDate | 2012 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/725332022-09-29T19:46:58Z Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA Pang, Bo McFaline, Jose Luis Burgis, Nicholas E. Taghizadeh, Koli Sullivan, Matthew R. Elmquist, C. Eric Cunningham, Richard P. Dedon, Peter C. Dong, Min, 1968- Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Dedon, Peter C. Pang, Bo McFaline, Jose Luis Dong, Min Taghizadeh, Koli Sullivan, Matthew R. Elmquist, C. Eric Dedon, Peter C. Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelated mechanisms, including hydrolysis, nitrosative chemistry, and deaminase enzymes. Here we present a fourth mechanism contributing to the burden of nucleobase deamination: incorporation of hypoxanthine and xanthine into DNA and RNA caused by defects in purine nucleotide metabolism. Using Escherichia coli and Saccharomyces cerevisiae with defined mutations in purine metabolism in conjunction with analytical methods for quantifying deaminated nucleobases in DNA and RNA, we observed large increases (up to 600-fold) in hypoxanthine in both DNA and RNA in cells unable to convert IMP to XMP or AMP (IMP dehydrogenase, guaB; adenylosuccinate synthetase, purA, and ADE12), and unable to remove dITP/ITP and dXTP/XTP from the nucleotide pool (dITP/XTP pyrophosphohydrolase, rdgB and HAM1). Conversely, modest changes in xanthine levels were observed in RNA (but not DNA) from E. coli lacking purA and rdgB and the enzyme converting XMP to GMP (GMP synthetase, guaA). These observations suggest that disturbances in purine metabolism caused by known genetic polymorphisms could increase the burden of mutagenic deaminated nucleobases in DNA and interfere with gene expression and RNA function, a situation possibly exacerbated by the nitrosative stress of concurrent inflammation. The results also suggest a mechanistic basis for the pathophysiology of human inborn errors of purine nucleotide metabolism. National Institutes of Health (U.S.) (Grant number CA116318) National Institutes of Health (U.S.) (Grant number CA026731) National Institutes of Health (U.S.) (Grant number ES002109) National Institutes of Health (U.S.) (Grant number RR0154464) 2012-09-05T19:30:39Z 2012-09-05T19:30:39Z 2012-02 2011-11 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/72533 Pang, B. et al. “Defects in Purine Nucleotide Metabolism Lead to Substantial Incorporation of Xanthine and Hypoxanthine into DNA and RNA.” Proceedings of the National Academy of Sciences 109.7 (2012): 2319–2324. Copyright ©2012 by the National Academy of Sciences https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0002-4607-5337 en_US http://dx.doi.org/10.1073/pnas.1118455109 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences PNAS |
| spellingShingle | Pang, Bo McFaline, Jose Luis Burgis, Nicholas E. Taghizadeh, Koli Sullivan, Matthew R. Elmquist, C. Eric Cunningham, Richard P. Dedon, Peter C. Dong, Min, 1968- Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA |
| title | Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA |
| title_full | Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA |
| title_fullStr | Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA |
| title_full_unstemmed | Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA |
| title_short | Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA |
| title_sort | defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into dna and rna |
| url | http://hdl.handle.net/1721.1/72533 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0002-4607-5337 |
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