title: DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis.
abstract: Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. DOI:http://dx.doi.org/10.7554/eLife.00534.001.
authors.affiliation: Protein and Nucleic Acid Chemistry Division , Medical Research Council Laboratory of Molecular Biology , Cambridge , United Kingdom.
authors.forename: Benjamin Jm
authors.initials: BJ
authors.lastname: Taylor
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Stebbings
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Cristina
authors.initials: C
authors.lastname: Rada
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Michael S
authors.initials: MS
authors.lastname: Neuberger
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D011506:Proteins / Q000235:genetics*
chemical_list: D015778:Minor Histocompatibility Antigens; D011506:Proteins; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase
keywords: AID/APOBECs; Cancer; Cytidine deamination; DNA deamination; Human; Hypermutation; Kataegis; S. cerevisiae