Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA
Abstract Background APOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum...
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | BMC Genomics |
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| Online Access: | http://link.springer.com/article/10.1186/s12864-019-6216-x |
| _version_ | 1828843314678333440 |
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| author | Vincent Caval Wenjuan Jiao Noémie Berry Pierre Khalfi Emmanuelle Pitré Valérie Thiers Jean-Pierre Vartanian Simon Wain-Hobson Rodolphe Suspène |
| author_facet | Vincent Caval Wenjuan Jiao Noémie Berry Pierre Khalfi Emmanuelle Pitré Valérie Thiers Jean-Pierre Vartanian Simon Wain-Hobson Rodolphe Suspène |
| author_sort | Vincent Caval |
| collection | DOAJ |
| description | Abstract Background APOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum of placental mammals have been shown to introduce somatic mutations into nuclear DNA of cancer genomes, we explored the mutagenic threat of A1 cytidine deaminases to chromosomal DNA. Results Molecular cloning and expression of various A1 enzymes reveal that the cow, pig, dog, rabbit and mouse A1 have an intracellular ssDNA substrate specificity. However, among all the enzymes studied, mouse A1 appears to be singular, being able to introduce somatic mutations into nuclear DNA with a clear 5’TpC editing context, and to deaminate 5-methylcytidine substituted DNA which are characteristic features of the cancer related mammalian A3A and A3B enzymes. However, mouse A1 activity fails to elicit formation of double stranded DNA breaks, suggesting that mouse A1 possess an attenuated nuclear DNA mutator phenotype reminiscent of human A3B. Conclusions At an experimental level mouse APOBEC1 is remarkable among 12 mammalian A1 enzymes in that it represents a source of somatic mutations in mouse genome, potentially fueling oncogenesis. While the order Rodentia is bereft of A3A and A3B like enzymes it seems that APOBEC1 may well substitute for it, albeit remaining much less active. This modifies the paradigm that APOBEC3 and AID enzymes are the sole endogenous mutator enzymes giving rise to off-target editing of mammalian genomes. |
| first_indexed | 2024-12-12T20:43:31Z |
| format | Article |
| id | doaj.art-00a6046ee2244f53afae207b0b6b99ea |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-12T20:43:31Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-00a6046ee2244f53afae207b0b6b99ea2022-12-22T00:12:39ZengBMCBMC Genomics1471-21642019-11-0120111210.1186/s12864-019-6216-xMouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNAVincent Caval0Wenjuan Jiao1Noémie Berry2Pierre Khalfi3Emmanuelle Pitré4Valérie Thiers5Jean-Pierre Vartanian6Simon Wain-Hobson7Rodolphe Suspène8Molecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurMolecular Retrovirology Unit, Institut PasteurAbstract Background APOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum of placental mammals have been shown to introduce somatic mutations into nuclear DNA of cancer genomes, we explored the mutagenic threat of A1 cytidine deaminases to chromosomal DNA. Results Molecular cloning and expression of various A1 enzymes reveal that the cow, pig, dog, rabbit and mouse A1 have an intracellular ssDNA substrate specificity. However, among all the enzymes studied, mouse A1 appears to be singular, being able to introduce somatic mutations into nuclear DNA with a clear 5’TpC editing context, and to deaminate 5-methylcytidine substituted DNA which are characteristic features of the cancer related mammalian A3A and A3B enzymes. However, mouse A1 activity fails to elicit formation of double stranded DNA breaks, suggesting that mouse A1 possess an attenuated nuclear DNA mutator phenotype reminiscent of human A3B. Conclusions At an experimental level mouse APOBEC1 is remarkable among 12 mammalian A1 enzymes in that it represents a source of somatic mutations in mouse genome, potentially fueling oncogenesis. While the order Rodentia is bereft of A3A and A3B like enzymes it seems that APOBEC1 may well substitute for it, albeit remaining much less active. This modifies the paradigm that APOBEC3 and AID enzymes are the sole endogenous mutator enzymes giving rise to off-target editing of mammalian genomes.http://link.springer.com/article/10.1186/s12864-019-6216-xAPOBEC1Cytidine deaminaseSomatic mutationsNuclear DNACancer |
| spellingShingle | Vincent Caval Wenjuan Jiao Noémie Berry Pierre Khalfi Emmanuelle Pitré Valérie Thiers Jean-Pierre Vartanian Simon Wain-Hobson Rodolphe Suspène Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA BMC Genomics APOBEC1 Cytidine deaminase Somatic mutations Nuclear DNA Cancer |
| title | Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA |
| title_full | Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA |
| title_fullStr | Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA |
| title_full_unstemmed | Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA |
| title_short | Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA |
| title_sort | mouse apobec1 cytidine deaminase can induce somatic mutations in chromosomal dna |
| topic | APOBEC1 Cytidine deaminase Somatic mutations Nuclear DNA Cancer |
| url | http://link.springer.com/article/10.1186/s12864-019-6216-x |
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