Mutual regulation between cell cycle and transcription termination factor TTF2

Most transcriptional activities are silent during mitosis and reactivated upon mitotic exit; however, the underlying detailed mechanisms are still largely unknown. We revealed that the cell cycle regulatory machinery anaphase-promoting complex/cyclosome (APC/C) and mitotic checkpoint complex (MCC) are coupled with transcription termination to modulate cell cycle progression via the transcription termination factor TTF2. The protein level of TTF2 oscillated during cell cycle progression, and increased in the S and G2/M phases while maintaining a low level in late mitosis and the G1 phase. Knockdown of TTF2 induced G2/M arrest, while overexpression of TTF2 accelerated the M/G1 transition and promoted cell proliferation. Mechanistic studies revealed that TTF2 was ubiquitinated by APC/C^CDH1 and targeted for proteasomal degradation. Interestingly, TTF2 bound to CDC20 and prevented MCC formation during normal mitosis. However, TTF2 was degraded by APC/C^CDH1 when the cell encountered persistent G2/M arrest, which would release CDC20 and promote the assembly of MCC. Additionally, TTF2 was overexpressed in almost all solid tumors and correlated with poor survival in patients with several kinds of solid tumors. Thus, these findings establish a link between transcription termination and cell cycle regulation, revealing an unexpected mechanism by which TTF2 plays dual roles in mitosis by binding to CDH1 and CDC20 to balance the activation of APC/C and MCC.