Genetic fusions favor tumorigenesis through degron loss in oncogenes.
Genetic fusions favor tumorigenesis through degron loss in oncogenes.
复制标题
DOI：
10.1038/s41467-021-26871-y
复制
发表时间：
2021-11-18
影响因子：
16.6
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Liu J;Tokheim C;Lee JD;Gan W;North BJ;Liu XS;Pandolfi PP;Wei W
染色体重排可以产生由两个不同基因序列组成的遗传融合，其中许多基因序列与肿瘤的发生和发展有关。我们的研究提出了一个模型，致癌基因融合经常改变蛋白质的稳定性，通过交换蛋白质降解信号（降解决定子）之间的基因序列。癌症基因组图谱（TCGA）的计算分析确定了2，406例降解决定子交换事件，并揭示了由于融合导致的降解决定子丢失而导致的癌基因稳定化的富集。此外，我们确定并实验验证了一些经常性的融合，如BCR-ABL，CCDC 6-RET和PML-RARA融合，通过交换内部降解决定子扰乱蛋白质的稳定性。同样，我们还验证了EGFR或RAF 1融合可以通过丢失计算预测的C-末端降解决定子来稳定。因此，与通过启动子交换增强的癌基因转录互补，我们的降解决定子丢失模型说明了复发性融合蛋白在驱动肿瘤发生中的另一种一般机制。基因融合对降解决定子（degron）的影响尚未得到充分研究，降解决定子是泛素介导的蛋白质降解的基序。在这里，作者分析了影响泛癌症基因组学数据中降解决定子的融合基因，验证了它们的功能影响，并发现了内部和C末端降解决定子损失的富集。
Chromosomal rearrangements can generate genetic fusions composed of two distinct gene sequences, many of which have been implicated in tumorigenesis and progression. Our study proposes a model whereby oncogenic gene fusions frequently alter the protein stability of the resulting fusion products, via exchanging protein degradation signal (degron) between gene sequences. Computational analyses of The Cancer Genome Atlas (TCGA) identify 2,406 cases of degron exchange events and reveal an enrichment of oncogene stabilization due to loss of degrons from fusion. Furthermore, we identify and experimentally validate that some recurrent fusions, such as BCR-ABL, CCDC6-RET and PML-RARA fusions, perturb protein stability by exchanging internal degrons. Likewise, we also validate that EGFR or RAF1 fusions can be stabilized by losing a computationally-predicted C-terminal degron. Thus, complementary to enhanced oncogene transcription via promoter swapping, our model of degron loss illustrates another general mechanism for recurrent fusion proteins in driving tumorigenesis. The impact of genetic fusions on degrons, which are motifs for ubiquitin-mediated protein degradation, has not been fully explored. Here, the authors analyse fusion genes affecting degrons in pan-cancer genomics data, validate their functional impact and find enrichment for both internal and C-terminal degron losses.
登录
查看更多内容
影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
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
作者：
Gan W;Dai X;Lunardi A;Li Z;Inuzuka H;Liu P;Varmeh S;Zhang J;Cheng L;Sun Y;Asara JM;Beck AH;Huang J;Pandolfi PP;Wei W
通讯作者：
Wei W
影响因子：
11.2
作者：
Burslem, George M.;Schultz, Anna Reister;Crews, Craig M.
通讯作者：
Crews, Craig M.
影响因子：
10.1
作者：
Godavarthy, Parimala Sonika;Kumar, Rahul;Krause, Daniela S.
通讯作者：
Krause, Daniela S.