APOBEC3B is an enzymatic source of mutation in breast cancer

Michael B. Burns, Lela Lackey, Michael A. Carpenter, Anurag Rathore, Allison M. Land, Brandon Leonard, Eric W. Refsland, Delshanee Kotandeniya, Natalia Tretyakova, Jason B. Nikas, Douglas Yee, Nuri A. Temiz, Duncan E. Donohue, Rebecca M. Mcdougle, William L. Brown, Emily K. Law, Reuben S. Harris

Research output: Contribution to journalArticle

399 Citations (Scopus)

Abstract

Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.

Original languageEnglish (US)
Pages (from-to)366-370
Number of pages5
JournalNature
Volume494
Issue number7437
DOIs
StatePublished - Feb 21 2013

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Breast Neoplasms
Mutation
Cytosine Deaminase
Genome
Cell Line
Neoplasms
Deamination
Uracil
Cytosine
DNA
DNA Fragmentation
Mutation Rate
Cell Extracts
DNA Damage
Cell Cycle
Cell Death
Messenger RNA
Proteins

Cite this

Burns, M. B., Lackey, L., Carpenter, M. A., Rathore, A., Land, A. M., Leonard, B., ... Harris, R. S. (2013). APOBEC3B is an enzymatic source of mutation in breast cancer. Nature, 494(7437), 366-370. https://doi.org/10.1038/nature11881

APOBEC3B is an enzymatic source of mutation in breast cancer. / Burns, Michael B.; Lackey, Lela; Carpenter, Michael A.; Rathore, Anurag; Land, Allison M.; Leonard, Brandon; Refsland, Eric W.; Kotandeniya, Delshanee; Tretyakova, Natalia; Nikas, Jason B.; Yee, Douglas; Temiz, Nuri A.; Donohue, Duncan E.; Mcdougle, Rebecca M.; Brown, William L.; Law, Emily K.; Harris, Reuben S.

In: Nature, Vol. 494, No. 7437, 21.02.2013, p. 366-370.

Research output: Contribution to journalArticle

Burns, MB, Lackey, L, Carpenter, MA, Rathore, A, Land, AM, Leonard, B, Refsland, EW, Kotandeniya, D, Tretyakova, N, Nikas, JB, Yee, D, Temiz, NA, Donohue, DE, Mcdougle, RM, Brown, WL, Law, EK & Harris, RS 2013, 'APOBEC3B is an enzymatic source of mutation in breast cancer', Nature, vol. 494, no. 7437, pp. 366-370. https://doi.org/10.1038/nature11881
Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature. 2013 Feb 21;494(7437):366-370. https://doi.org/10.1038/nature11881
Burns, Michael B. ; Lackey, Lela ; Carpenter, Michael A. ; Rathore, Anurag ; Land, Allison M. ; Leonard, Brandon ; Refsland, Eric W. ; Kotandeniya, Delshanee ; Tretyakova, Natalia ; Nikas, Jason B. ; Yee, Douglas ; Temiz, Nuri A. ; Donohue, Duncan E. ; Mcdougle, Rebecca M. ; Brown, William L. ; Law, Emily K. ; Harris, Reuben S. / APOBEC3B is an enzymatic source of mutation in breast cancer. In: Nature. 2013 ; Vol. 494, No. 7437. pp. 366-370.
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