NKU Research Team Revealed the Biochemical Mechanism for DNA Damage-Inducible RNA Pol II Release Regulated by Paf1 Complex


Recently, the research team led by professor Long Jiafu of the College of Life Sciences and State Key Laboratory of Medical Chemical Biology of Nankai University, achieved important progress in the research of the function of PAF1C. The paper introducing the achievements was published in PANS, with the title of "The Paf1 complex is required for RNA polymerase II removal in response to DNA damage".

The paper revealed a very important multi-step route for RNAPII release regulated by PAF1C, i.e. after DNA damage, PAF1C participates in the regulation of the total intracellular RNAPII protein level thorugh promoting Elongin-Cullin E3 ubiquitin ligase complex-mediated Rpb1(the largest subunit in RNAPII) ubiquitination and proteasome degradation to further. Step 1: Without DNA damage, the interaction between Spt5-pCTR (phosphorylated C-terminal Repeat) and Rtf1 subunit in PAF1C (via Plus3 structural domain) helps PAF1C be recruited to RNAPII transcription machine for fast transcription elongation; Step 2: With DNA damage, RNAPII transcription machine stagnates at the damaged DNA position to recruit the dephosphorylated Spt5-pCTR of unknown PPase and destruct interaction between Rtf1 and Spt5, which may promote the exchange between Spt5 and repair initiation factor Rad26; Step 3: Rad26 is bound to damaged DNA position via RNAPII dependency and replaces Spt4/5 complex, the transcription elongation factor; Step 4: Coupled with Leo1 subunit in PAF1C, Rad26 recruits more PAF1C and Def1 to stagnate at RNAPII transcription machine; Step 5: Finally, the complete PAF1C and Rad26, formed by Ctr9 mediation, together with Def1 specifically recruit RNAPII targeted and stagnated by Elongin-Cullin complex, and promote Rpb1 ubiquitination and proteasome degradation. These research results provide insight from the perspective of the biochemical mechanism for the function in PAF1C's coordination of the exchange between Spt5 and Rad26 and RNAPII release after DNA damage. Meanwhile, such results also lay a preliminary experiment basis for DNA damage-based chemotherapeutic drug research and development or drug resistant mechanism research of relevant medicines.

Professor Long Jiafu is the corresponding author of the paper, and PhD graduates Chen Feilong and Liu Beibei are the first authors of the paper.

Paper link: https://www.pnas.org/doi/10.1073/pnas.2207332119

(Edited and translated by Nankai News Team)