Document Detail


APOBEC3B is an enzymatic source of mutation in breast cancer.
MedLine Citation:
PMID:  23389445     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-02-06
Journal Detail:
Title:  Nature     Volume:  494     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-21     Completed Date:  2013-03-12     Revised Date:  2014-05-29    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  366-70     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Biocatalysis
Breast Neoplasms / enzymology*,  genetics*,  pathology
Cell Death
Cell Line, Tumor
Cytidine Deaminase / genetics,  metabolism*
DNA Damage / genetics
DNA Fragmentation
DNA, Neoplasm / genetics,  metabolism
Deamination
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Histones / metabolism
Humans
Mutagenesis* / genetics
Phenotype
Point Mutation* / genetics
Tumor Suppressor Protein p53 / genetics,  metabolism
Up-Regulation
Uracil / metabolism
Grant Support
ID/Acronym/Agency:
1UL1RR033183/RR/NCRR NIH HHS; F31 DA033186/DA/NIDA NIH HHS; F31 DA033186/DA/NIDA NIH HHS; F32 GM095219/GM/NIGMS NIH HHS; KL2 RR033182/RR/NCRR NIH HHS; P01 GM091743/GM/NIGMS NIH HHS; P01 GM091743/GM/NIGMS NIH HHS; P30 CA77598/CA/NCI NIH HHS; P50 CA101955/CA/NCI NIH HHS; R01 AI064046/AI/NIAID NIH HHS; R01 AI064046/AI/NIAID NIH HHS; T32 AI083196/AI/NIAID NIH HHS; T32 AI083196/AI/NIAID NIH HHS; T32 CA009138/CA/NCI NIH HHS; T32 CA009138/CA/NCI NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/DNA, Neoplasm; 0/H2AFX protein, human; 0/Histones; 0/Tumor Suppressor Protein p53; 56HH86ZVCT/Uracil; EC 3.5.4.5/APOBEC3B protein, human; EC 3.5.4.5/Cytidine Deaminase
Comments/Corrections
Comment In:
Nat Rev Cancer. 2013 Apr;13(4):220-1   [PMID:  23486239 ]
Erratum In:
Nature. 2013 Oct 24;502(7472):580

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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