title: Error-free versus mutagenic processing of genomic uracil--relevance to cancer.
abstract: Genomic uracil is normally processed essentially error-free by base excision repair (BER), with mismatch repair (MMR) as an apparent backup for U:G mismatches. Nuclear uracil-DNA glycosylase UNG2 is the major enzyme initiating BER of uracil of U:A pairs as well as U:G mismatches. Deficiency in UNG2 results in several-fold increases in genomic uracil in mammalian cells. Thus, the alternative uracil-removing glycosylases, SMUG1, TDG and MBD4 cannot efficiently complement UNG2-deficiency. A major function of SMUG1 is probably to remove 5-hydroxymethyluracil from DNA with general back-up for UNG2 as a minor function. TDG and MBD4 remove deamination products U or T mismatched to G in CpG/mCpG contexts, but may have equally or more important functions in development, epigenetics and gene regulation. Genomic uracil was previously thought to arise only from spontaneous cytosine deamination and incorporation of dUMP, generating U:G mismatches and U:A pairs, respectively. However, the identification of activation-induced cytidine deaminase (AID) and other APOBEC family members as DNA-cytosine deaminases has spurred renewed interest in the processing of genomic uracil. Importantly, AID triggers the adaptive immune response involving error-prone processing of U:G mismatches, but also contributes to B-cell lymphomagenesis. Furthermore, mutational signatures in a substantial fraction of other human cancers are consistent with APOBEC-induced mutagenesis, with U:G mismatches as prime suspects. Mutations can be caused by replicative polymerases copying uracil in U:G mismatches, or by translesion polymerases that insert incorrect bases opposite abasic sites after uracil-removal. In addition, kataegis, localized hypermutations in one strand in the vicinity of genomic rearrangements, requires APOBEC protein, UNG2 and translesion polymerase REV1. What mechanisms govern error-free versus error prone processing of uracil in DNA remains unclear. In conclusion, genomic uracil is an essential intermediate in adaptive immunity and innate antiviral responses, but may also be a fundamental cause of a wide range of malignancies.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway. Electronic address: hans.krokan@ntnu.no.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway; Department of Computer and Information Science, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Sætrom
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway.
authors.forename: Per Arne
authors.initials: PA
authors.lastname: Aas
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway; St. Olav's Hospital, Trondheim University Hospital, NO-7006 Trondheim, Norway.
authors.forename: Henrik Sahlin
authors.initials: HS
authors.lastname: Pettersen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway.
authors.forename: Bodil
authors.initials: B
authors.lastname: Kavli
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
mesh_terms: D000071479:APOBEC-1 Deaminase; D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D003596:Cytosine / Q000378:metabolism; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D014498:Uracil / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099270:Y-Family DNA Polymerases
chemical_list: D000071479:APOBEC-1 Deaminase; D003564:Cytidine Deaminase; D003596:Cytosine; D045647:DNA Glycosylases; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D014498:Uracil; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C429004:REV1 protein, human; D000099270:Y-Family DNA Polymerases; C492570:CCNO protein, human; C000605089:APOBEC1 protein, human
keywords: AID/APOBEC; Adaptive immunity; Base excision repair; Cancer; Genomic uracil; Mutational signatures