NEIL2 regulates RNA polymerase II dynamics to suppress transcription–replication conflicts in pancreatic cancer
Year: 2026
Type: preprint
Abstract: ABSTRACT Transcription–replication conflicts (TRCs) arise from spatiotemporal interference between replication and transcription machinery and contribute to genome instability in cancer cells. In pancreatic ductal adenocarcinoma (PDAC) cells, oncogenic KRAS drives TRC formation, and base excision repair (BER) contributes to TRC resolution as an adaptive response. Here, we show that TRCs are enriched in pancreatic tumor sections from patients and are associated with malignant progression. We identify NEIL2, a bifunctional DNA glycosylase in the BER pathway, as a critical regulator of TRCs in PDAC cells. Mechanistically, NEIL2 loss causes aberrant RNA polymerase II (RNAPII) occupancy at transcription start sites and downstream of transcription end sites. Dysregulated RNAPII dynamics promote R-loop-dependent and -independent TRCs contributing to replication stress, DNA damage, and impaired cancer cell proliferation. Notably, the DNA-binding motif of NEIL2 necessary for canonical BER function is dispensable for TRC regulation. Together, these findings reveal an unrecognized role for NEIL2 in regulating RNAPII dynamics and mitigating TRCs in pancreatic cancer cells.
Institutions: City Of Hope National Medical Center, City of Hope, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Cedars-Sinai Medical Center, University of California, Los Angeles, UCLA Jonsson Comprehensive Cancer Center, University of California, Riverside
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223054986