The lariat RNA debranching enzyme DBR1 enhances HIF-1 signaling and chemoresistance at the expense of lariat RNA processing.

Abstract

Severely hypoxic microenvironments that induce cell-cycle arrest and chemoresistance are frequently found within solid tumors. Since hypoxia-inducible factor 1 (HIF-1) serves as a central transcription factor for cellular adaptation to oxygen deprivation, identification of novel regulators of HIF-1 activity may provide novel therapeutic opportunities. Here, we performed a genome-wide screening for novel positive regulators of HIF-1 and identified debranching RNA lariats 1 (DBR1). DBR1 was found to form a complex with the regulatory subunit of HIF-1, HIF-1α, promote its nuclear accumulation and recruitment to hypoxia-response elements (HREs), and enhance HIF-1-dependent transcription without altering HIF-1α mRNA or protein levels. Notably, a catalytic mutant of DBR1 lacking debranching activity retained the ability to activate HIF-1. Interestingly, under hypoxic conditions, HIF-1 redirected DBR1 from its canonical RNA debranching function toward HIF-1-dependent transcriptional regulation, resulting in reduced debranching activity, lariat RNA accumulation, and impaired cell growth. Furthermore, DBR1 contributed to hypoxia-induced resistance to multiple conventional chemotherapeutic agents. Collectively, our findings support a model in which HIF-1 functionally redistributes DBR1 from lariat RNA processing toward HIF-1-dependent transcription, thereby promoting HIF-1 signaling and chemoresistance at the expense of lariat RNA processing.