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APOBEC3B is an enzymatic source of mutation in breast cancer

机译：APOBEC3B是乳腺癌中突变的酶促来源

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摘要

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.
机译：癌症的发展需要几个突变，而基因组测序表明，包括乳腺癌在内的许多癌症都具有由C到T转换为主的体细胞突变谱。这些突变大多数发生在整个基因组中水解不利的非甲基化胞嘧啶上，有时会聚集在一起。在这里，我们显示DNA胞嘧啶脱氨酶APOBEC3B是这些突变的可能来源。在大多数原发性乳腺肿瘤和乳腺癌细胞系中，APOBEC3B信使RNA上调。表达高水平APOBEC3B的肿瘤的突变是表达低水平的肿瘤的两倍，并且更可能在TP53中发生突变。内源性APOBEC3B蛋白主要是核蛋白，是乳腺癌细胞系提取物中DNA C到U编辑活性的唯一可检测来源。击倒实验表明，内源性APOBEC3B与基因组尿嘧啶水平增加，突变频率增加和C-T转换有关。此外，诱导的APOBEC3B过度表达会导致细胞周期偏离，细胞死亡，DNA片段化，γ-H2AX积累和C到T突变。我们的数据提出了一种模型，其中APOBEC3B催化的脱氨作用为乳腺癌提供了DNA损伤的长期来源，可以选择TP53失活，并解释某些肿瘤如何快速发展并表现出异质性。

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  • 来源
    《Nature》 |2013年第7437期|366-370|共5页
  • 作者

    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;

  • 作者单位

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA,Microbiology, Cancer Biology and Immunology Graduate Program, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    ln Silico Research Centers of Excellence, Advanced Biomedical Computing Center, Information Systems Program, SAIC-Frederick inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA;

    ln Silico Research Centers of Excellence, Advanced Biomedical Computing Center, Information Systems Program, SAIC-Frederick inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA;

    Biochemistry, Molecular Biology and Biophysics Department, University of Minnesota, Minneapolis, Minnesota 55455, USA,Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA,Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA,Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA,Microbiology, Cancer Biology and Immunology Graduate Program, University of Minnesota, Minneapolis, Minnesota 55455, USA;

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