RTF1 is a transcription elongation factor that functions as a component of the PAF1 complex (PAF1C), regulating RNA polymerase II transcription through multiple mechanisms 1. RTF1 facilitates histone H2B monoubiquitination (H2Bub1) and histone H3 lysine-4 trimethylation (H3K4me3), modifications conserved from yeast to humans 12. The protein contains a functionally important Plus3 domain that binds single-stranded DNA and is critical for transcriptional activation 3. Notably, human RTF1 operates largely independently of PAF1C, distinct from the yeast homolog 4. RTF1 regulates circadian rhythms by enhancing CLK occupancy and H3K4me3 deposition at clock gene promoters, with mechanisms conserved in mammals 5. Structurally, RTF1 contains a histone modification domain (HMD) sufficient to promote H2Bub1 independently of core PAF1C components 6. Disease relevance includes associations with ulcerative colitis risk, where RTF1 deficiency impairs Th17 cell differentiation through disrupted H2Bub1-mediated epigenetic regulation 2. RTF1 mutations also contribute to primary microcephaly, with functional studies demonstrating reduced neural progenitor cell proliferation 7. Elongin binding to Pol II is incompatible with PAF1C and RTF1 association, indicating selective recruitment during transcription 8.