Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
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PMID:CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. 3245 76

The negative elongation factor (NELF) is a four-subunit protein complex (NELF-E, NELF-A, NELF-B and NELF-C/D) that negatively regulates transcription elongation of RNA polymerase II (Pol II). Interestingly, upregulation of NELF-E subunit promotes hepatocellular carcinoma (HCC) and pancreatic cancer. In addition, we have previously shown that NELF complex fosters double-strand break (DSB)-induced transcription silencing and promotes homology-directed repair (HDR). However, the mechanisms underlying NELF-E regulation of HDR of DSBs remain unknown. Here, we show that NELF-E interacts with BRCA1 and promotes its recruitment to laser-microirradiated sites and facilitates ionizing radiation-induced foci (IRIF) of BRCA1 in HCC cells (Hep3B). The reduction in BRCA1 IRIF is accompanied by decreased RAD51 IRIF. A corollary to this, NELF-E-deficient Hep3B cells exhibit defective HDR of chromosomal DSBs induced by CRISPR-Cas9 system. Consequently, the disruption of NELF complex integrity, by NELF-E downregulation, sensitizes Hep3B cells to PARP inhibition. Altogether, our results suggest that NELF promotes HDR by facilitating BRCA1 and RAD51 IRIF formation and identify NELF complex as a novel synthetic lethal partner of PARP1.
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PMID:NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition. 3324 88


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