Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer.
Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer.
复制标题
将KMT2C/MLL3募集到DNA损伤部位介导DNA损伤反应并调节癌症中的PARP抑制剂敏感性。
DOI：
10.1158/0008-5472.can-21-0688
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发表时间：
2021-06-15
期刊：
影响因子：
11.2
通讯作者：
Sun P
中科院分区：
文献类型：
--
作者：
Chang A;Liu L;Ashby JM;Wu D;Chen Y;O'Neill SS;Huang S;Wang J;Wang G;Cheng D;Tan X;Petty WJ;Pasche BC;Xiang R;Zhang W;Sun P
当募集到启动子时，组蛋白3赖氨酸4（H3 K4）甲基转移酶KMT 2（KMT 2A-D）通过经由H3 K4甲基化打开染色质来激活转录。在这里，我们报告说，KMT 2突变频繁发生在非小细胞肺癌（NSCLC），并与高突变负荷和生存率低。KMT 2C通过Ago 2和小的非编码DNA损伤反应RNA直接募集到DNA损伤位点来调节DNA损伤反应（DDR），在那里它介导H3 K4甲基化、染色质松弛、DDR因子的二次募集和DDR信号沿着染色质的扩增。此外，通过破坏同源重组（HR）介导的DNA修复，KMT 2C/D突变使NSCLC对聚（ADP-核糖）聚合酶抑制剂（PARPi）敏感，由于BRCA 1/2突变率较低，PARPi在NSCLC中的疗效尚不清楚。这些结果证明了KMT 2C在DDR中的一种新的、不依赖于转录的作用，并确定了高频KMT 2C/D突变作为NSCLC和其他罕见BRCA 1/2突变的癌症中PARPi治疗急需的生物标志物。
When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here we report that KMT2 mutations occur frequently in non-small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)-mediated DNA repair, KMT2C/D mutations sensitized NSCLC to Poly(ADP-Ribose) Polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low BRCA1/2 mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency KMT2C/D mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent BRCA1/2 mutations.