Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumors in vivo.
Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumors in vivo.
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RAD18介导特定的突变信号，并在体内塑造致癌物质诱导的肿瘤的基因组图景。
作者：
Lou J;Yang Y;Gu Q;Price BA;Qiu Y;Fedoriw Y;Desai S;Mose LE;Chen B;Tateishi S;Parker JS;Vaziri C;Wu D
E3泛素连接酶Rad18促进损伤耐受和易出错的DNA复制模式，称为跨病变合成，在癌症中被病理激活。然而，脊椎动物Rad18对癌症基因组的影响尚不清楚。为了确定Rad18如何影响体内突变，我们开发并实施了一种新的计算管道来分析致癌物质（7,12 -二甲基苯[a]蒽，DMBA）诱导的Rad18+/+和Rad18 - / -小鼠皮肤肿瘤的基因组。我们发现Rad18介导了以高水平的A(T)>T(A)单核苷酸变异（SNVs）为特征的特异性突变特征。在Rad18−/-肿瘤中，出现了另一种突变模式，其特征是缺失bbb40bp的数量增加。与带注释的人类突变特征的比较表明，COSMIC特征22在Rad18+/+肿瘤中占主导地位，而Rad18−/−肿瘤的特征是COSMIC特征3 （brca突变肿瘤的标志）的贡献增加。对癌症基因组图谱的分析显示，RAD18的表达与高SNV负荷密切相关，表明RAD18也促进了人类癌症的突变。综上所述，我们的研究结果表明，Rad18促进体内突变，调节肿瘤细胞中DNA修复途径的选择，并介导人类肿瘤中存在的特异性突变特征。
The E3 ubiquitin ligase Rad18 promotes a damage-tolerant and error-prone mode of DNA replication termed trans-lesion synthesis that is pathologically activated in cancer. However, the impact of vertebrate Rad18 on cancer genomes is not known. To determine how Rad18 affects mutagenesis in vivo, we have developed and implemented a novel computational pipeline to analyze genomes of carcinogen (7, 12-Dimethylbenz[a]anthracene, DMBA)-induced skin tumors from Rad18+/+ and Rad18−/− mice. We show that Rad18 mediates specific mutational signatures characterized by high levels of A(T)>T(A) single nucleotide variations (SNVs). In Rad18−/- tumors, an alternative mutation pattern arises, which is characterized by increased numbers of deletions >4 bp. Comparison with annotated human mutational signatures shows that COSMIC signature 22 predominates in Rad18+/+ tumors whereas Rad18−/− tumors are characterized by increased contribution of COSMIC signature 3 (a hallmark of BRCA-mutant tumors). Analysis of The Cancer Genome Atlas shows that RAD18 expression is strongly associated with high SNV burdens, suggesting RAD18 also promotes mutagenesis in human cancers. Taken together, our results show Rad18 promotes mutagenesis in vivo, modulates DNA repair pathway choice in neoplastic cells, and mediates specific mutational signatures that are present in human tumors.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
影响因子：
4.5
作者：
Hendel A;Krijger PH;Diamant N;Goren Z;Langerak P;Kim J;Reissner T;Lee KY;Geacintov NE;Carell T;Myung K;Tateishi S;D'Andrea A;Jacobs H;Livneh Z
通讯作者：
Livneh Z
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
16.6
作者：
Gao Y;Mutter-Rottmayer E;Greenwalt AM;Goldfarb D;Yan F;Yang Y;Martinez-Chacin RC;Pearce KH;Tateishi S;Major MB;Vaziri C
通讯作者：
Vaziri C
DOI：
10.1073/pnas.92.22.10422
发表时间：
1995-10-24
影响因子：
11.1
作者：
CHAKRAVARTI, D;PELLING, JC;ROGAN, EG
通讯作者：
ROGAN, EG