VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.
VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.
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DOI：
10.1172/jci.insight.158755
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发表时间：
2022-10-10
期刊：
影响因子：
8
通讯作者：
Hahn, William C.
中科院分区：
文献类型：
--
作者：
So, Jonathan;Mabe, Nathaniel W.;Englinger, Bernhard;Chow, Kin-Hoe;Moyer, Sydney M.;Yerrum, Smitha;Trissal, Maria C.;Marques, Joana G.;Kwon, Jason J.;Shim, Brian;Pal, Sangita;Panditharatna, Eshini;Quinn, Thomas;Schaefer, Daniel A.;Jeong, Daeun;Mayhew, David L.;Hwang, Justin;Beroukhim, Rameen;Ligon, Keith L.;Stegmaier, Kimberly;Filbin, Mariella G.;Hahn, William C.
当基因/蛋白质的丢失使癌细胞依赖于其剩余的蛋白质时，就会发生附带致死性。将基因组规模的CRISPR/Cas9功能丧失筛选与超过900种癌细胞系的RNA测序相结合，我们发现神经系统谱系的癌症，包括成人和儿童神经胶质瘤和神经母细胞瘤，需要核激酶牛痘相关激酶1（VRK 1）才能在体内存活。VRK 1依赖性与VRK 2的表达呈负相关。VRK 2敲除使细胞对VRK 1损失敏感，相反，VRK 2过表达在VRK 1损失的情况下增加细胞适应性。VRK 2启动子的DNA甲基化与人类神经母细胞瘤和成人及儿童胶质瘤中VRK 2的低表达相关。从机制上讲，VRK 1的耗竭减少了有丝分裂过程中自整合障碍因子的磷酸化，导致DNA损伤和凋亡。总之，这些研究将VRK 1鉴定为VRK 2启动子甲基化的成人和儿童胶质瘤和神经母细胞瘤中的合成致死靶点。
Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter–methylated adult and pediatric gliomas and neuroblastomas.
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影响因子：
3.3
作者：
Molitor TP;Traktman P
通讯作者：
Traktman P
影响因子：
3.7
作者：
BANHAM, AH;SMITH, GL
通讯作者：
SMITH, GL
DOI：
10.3791/55360
发表时间：
2017-03-07
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Lin GL;Monje M
通讯作者：
Monje M
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1126/science.aao4750
发表时间：
2018-04-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Filbin MG;Tirosh I;Hovestadt V;Shaw ML;Escalante LE;Mathewson ND;Neftel C;Frank N;Pelton K;Hebert CM;Haberler C;Yizhak K;Gojo J;Egervari K;Mount C;van Galen P;Bonal DM;Nguyen QD;Beck A;Sinai C;Czech T;Dorfer C;Goumnerova L;Lavarino C;Carcaboso AM;Mora J;Mylvaganam R;Luo CC;Peyrl A;Popović M;Azizi A;Batchelor TT;Frosch MP;Martinez-Lage M;Kieran MW;Bandopadhayay P;Beroukhim R;Fritsch G;Getz G;Rozenblatt-Rosen O;Wucherpfennig KW;Louis DN;Monje M;Slavc I;Ligon KL;Golub TR;Regev A;Bernstein BE;Suvà ML
通讯作者：
Suvà ML