RRC ID 66847
Author 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.
Title Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer.
Journal 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.
Volume 81(12)
Pages 3358-3373
Published 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
Human and Animal Cells LK-2(RCB1970) RERF-LC-AI(RCB0444) EBC-1(RCB1965) LC-1/sq-SF(RCB0438)