RRC ID |
66847
|
著者 |
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.
|
タイトル |
Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer.
|
ジャーナル |
Cancer Res
|
Abstract |
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. SIGNIFICANCE: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency KMT2C/D mutations as biomarkers for response to PARP inhibition in cancer.
|
巻・号 |
81(12)
|
ページ |
3358-3373
|
公開日 |
2021-6-15
|
DOI |
10.1158/0008-5472.CAN-21-0688
|
PII |
0008-5472.CAN-21-0688
|
PMID |
33853832
|
PMC |
PMC8260460
|
MeSH |
Animals
Apoptosis
Argonaute Proteins / genetics
Argonaute Proteins / metabolism
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Proliferation
DNA Damage*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Drug Resistance, Neoplasm*
Female
Gene Expression Regulation, Neoplastic*
Homologous Recombination
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Mice, Nude
Mutation*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Prognosis
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
IF |
9.727
|
リソース情報 |
ヒト・動物細胞 |
LK-2(RCB1970)
RERF-LC-AI(RCB0444)
EBC-1(RCB1965)
LC-1/sq-SF(RCB0438) |