title: The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53.
abstract: The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to IFN. Recently, a fewA3genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes, we show that under stress conditions and immune challenges, allA3genes are direct transcriptional targets of the tumor suppressor p53. Although the expression of mostA3genes (includingA3CandA3H) was stimulated by the activation of p53, treatment with the DNA-damaging agent doxorubicin or the p53 stabilizer Nutlin led to repression of theA3Bgene. Furthermore, p53 could enhance IFN type-I induction ofA3genes. Interestingly, overexpression of a group of tumor-associated p53 mutants inTP53-null cancer cells promotedA3Bexpression. These findings establish that the "guardian of the genome" role ascribed to p53 also extends to a unique component of the immune system, theA3genes, thereby integrating human immune and chromosomal stress responses into an A3/p53 immune axis.Implications:Activated p53 can integrate chromosomal stresses and immune responses through its influence on expression ofAPOBEC3genes, which are key components of the innate immune system that also influence genomic stability.Mol Cancer Res; 15(6); 735-44. ©2017 AACR.
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina. menendez@niehs.nih.gov.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
authors.forename: Thuy-Ai
authors.initials: TA
authors.lastname: Nguyen
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
authors.forename: Joyce
authors.initials: J
authors.lastname: Snipe
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
mesh_terms: D000071478:APOBEC Deaminases; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007370:Interferon Type I; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase