NELF coordinates Pol II transcription termination and DNA replication

Regulation of RNA polymerase II (Pol II) transcription is closely associated with cell proliferation. However, it remains unclear how the Pol II transcription program is altered in cancer to favour cell growth. Here, we find that gene expression of NELFCD, a known negative elongation factor, is up-regulated in colorectal tumours. To dissect the direct role of NELF-C on Pol II transcription in such cancer, we employed an auxin-dependent protein degradation system for NELF-C in combination with nascent transcript sequencing technologies. Strikingly, we demonstrate that the acute loss of NELF-C protein globally changes transcription elongation velocity and perturbs Pol II transcription termination. This results in Pol II transcription into DNA replication zones leading to transcription-replication conflict that may block the cell cycle in G1 or early S phase. We anticipate that NELF will be a potential therapeutic target to restrict colorectal cancers. Overall design: BrdU-IP sequencing in NELFC-AID and control DLD1 cells.This experiment was designed to examine the effect of NELFC depletion via the auxin-inducible degron system on the progression of DNA replication after release from nocodazole-induced G2 arrest.