Human APOBEC3B promotes tumor development in vivo including signature mutations and metastases.
Human APOBEC3B promotes tumor development in vivo including signature mutations and metastases.
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DOI：
10.1016/j.xcrm.2023.101211
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发表时间：
2023-10-17
影响因子：
14.3
通讯作者：
Harris, Reuben S.
中科院分区：
文献类型：
--
作者：
Durfee, Cameron;Temiz, Nuri Alpay;Levin-Klein, Rena;Argyris, Prokopios P.;Alsoe, Lene;Carracedo, Sergio;de la Vega, Alicia Alonso;Proehl, Joshua;Holzhauer, Anna M.;Seeman, Zachary J.;Liu, Xingyu;Lin, Yu-Hsiu T.;Vogel, Rachel I.;Sotillo, Rocio;Nilsen, Hilde;Harris, Reuben S.
抗病毒DNA胞嘧啶脱氨酶APOBEC 3B被认为是许多癌症的突变来源。然而，尽管多年的工作，因果关系尚未建立在体内。在这里，我们报告了一个小鼠模型，表达肿瘤样水平的人APOBEC 3B。表达全身APOBEC 3B的动物似乎发育正常。然而，成年雄性表现为不育，并且两种性别的老年动物显示出致癌、视觉和分子肿瘤异质性和转移的加速速率。原发性和转移性肿瘤均表现出TC二核苷酸基序中C至T突变频率增加，这与APOBEC 3B的既定生化活性一致。APOBEC 3B归因的单碱基取代突变的富集也与插入-缺失突变和结构变异水平的升高有关。所有这些表型都需要APOBEC 3B催化活性。总之，这些研究提供了因果关系证明，人类APOBEC 3B能够驱动体内肿瘤的发生和演变。人DNA脱氨酶APOBEC 3B在小鼠中的表达导致雄性不育催化活性的APOBEC 3B驱动肿瘤发展的加速速率表达APOBEC 3B的肿瘤表现出特征性的C-to-TCW基序中的T突变APOBEC 3B特征富集与indel水平增加呈正相关人抗病毒DNA胞嘧啶脱氨酶APOBEC 3B在小鼠中的表达加速肿瘤发展并促进肿瘤异质性，包括明显的表型差异，数千个签名单碱基取代突变（SBS 2），和更大规模的染色体畸变，包括插入-缺失突变和结构变异。
The antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many cancers. However, despite years of work, a causal relationship has yet to be established in vivo. Here, we report a murine model that expresses tumor-like levels of human APOBEC3B. Animals expressing full-body APOBEC3B appear to develop normally. However, adult males manifest infertility, and older animals of both sexes show accelerated rates of carcinogenesis, visual and molecular tumor heterogeneity, and metastasis. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Enrichment for APOBEC3B-attributable single base substitution mutations also associates with elevated levels of insertion-deletion mutations and structural variations. APOBEC3B catalytic activity is required for all of these phenotypes. Together, these studies provide a cause-and-effect demonstration that human APOBEC3B is capable of driving both tumor initiation and evolution in vivo. Expression of the human DNA deaminase APOBEC3B in mice causes male sterility Catalytically active APOBEC3B drives accelerated rates of tumor development APOBEC3B-expressing tumors exhibit signature C-to-T mutations in TCW motifs APOBEC3B signature enrichment associates positively with increased levels of indels Expression of the human antiviral DNA cytosine deaminase APOBEC3B in mice accelerates tumor development and promotes tumor heterogeneity including overt phenotypic differences, thousands of signature single base substitution mutations (SBS2), and larger-scale chromosomal aberrations including insertion-deletion mutations and structural variations.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
DOI：
10.1186/s13058-014-0498-3
发表时间：
2015-01-21
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Harris RS
通讯作者：
Harris RS
影响因子：
4.8
作者：
Doseth, Berit;Visnes, Torkild;Kavli, Bodil
通讯作者：
Kavli, Bodil