Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia.
Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia.
复制标题
DOI：
10.1038/s41586-018-0465-8
复制
发表时间：
2018-09
期刊：
影响因子：
64.8
通讯作者：
Mayr C
中科院分区：
文献类型：
--
作者：
Lee SH;Singh I;Tisdale S;Abdel-Wahab O;Leslie CS;Mayr C
DNA突变是已知的癌症驱动因素。在这里，我们研究了在癌症中上调的mRNA事件是否可以在功能上模拟遗传改变的结果。将3′-seq或RNA-seq应用于来自慢性淋巴细胞白血病（CLL; N = 59）的正常和恶性B细胞。我们发现在原代CLL细胞中截短的mRNA和蛋白质的广泛上调不是由遗传改变产生的，而是通过内含子聚腺苷酸化（IPA）发生的。IPA产生的截短mRNA是复发性的（N = 330），主要影响具有肿瘤抑制功能的基因。IPA产生的截短蛋白通常缺乏相应全长蛋白（DICER，FOXN 3）的肿瘤抑制功能，有几种甚至以致癌方式起作用（CARD 11，MGA，CHST 11）。在CLL中，通过异常mRNA加工导致的肿瘤抑制基因（TSG）失活比通过遗传事件导致的TSG丢失更普遍。我们进一步鉴定了新的TSG候选物，其在白血病中被IPA灭活，并且在实体瘤中被截短DNA突变灭活。这些基因在癌症中研究不足，因为它们的总体突变率低于众所周知的TSG。我们的研究结果表明，在癌症诊断中需要超越基因组分析，因为在DNA水平上沉默的mRNA事件是通过TSGs失活导致癌症发病的广泛因素。
DNA mutations are known cancer drivers. Here, we investigated if mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. 3′-seq or RNA-seq were applied to normal and malignant B cells from chronic lymphocytic leukemia (CLL; N = 59). We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but occurred through intronic polyadenylation (IPA). IPA-generated truncated mRNAs were recurrent (N = 330) and predominantly affected genes with tumor-suppressive functions. The IPA-generated truncated proteins often lack the tumor-suppressive functions of the corresponding full-length proteins (DICER, FOXN3), and several even acted in an oncogenic manner (CARD11, MGA, CHST11). In CLL, inactivation of tumor-suppressor genes (TSGs) through aberrant mRNA processing is substantially more prevalent than loss of TSGs through genetic events. We further identified novel TSG candidates that are inactivated by IPA in leukemia and by truncating DNA mutations in solid tumors. These genes are understudied in cancer as their overall mutation rates are lower than those of well-known TSGs. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through inactivation of TSGs.
登录
查看更多内容
影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
10.5
作者：
Lianoglou S;Garg V;Yang JL;Leslie CS;Mayr C
通讯作者：
Mayr C
影响因子：
3.7
作者：
Hoek KL;Samir P;Howard LM;Niu X;Prasad N;Galassie A;Liu Q;Allos TM;Floyd KA;Guo Y;Shyr Y;Levy SE;Joyce S;Edwards KM;Link AJ
通讯作者：
Link AJ
影响因子：
8.8
作者：
Karanth S;Zinkhan EK;Hill JT;Yost HJ;Schlegel A
通讯作者：
Schlegel A
影响因子：
56.9
作者：
Lenz, Georg;Davis, R. Eric;Staudt, Louis M.
通讯作者：
Staudt, Louis M.