NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition.

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.