PAN deadenylase ensures proper mitosis under conditions of microtubule stress by regulating spindle integrity and promoting cell survival

Abstract

AbstractThe Poly(A) Tail Length (PATL) of mRNAs of certain cell-cycle regulatory genes undergo significant trimming during M-phase, however the functional importance is unknown. The Ccr4-Not and PAN complexes account for the majority of cytoplasmic poly(A) deadenylation, however a role in M phase has not been described. We find that under conditions of microtubule stress in yeast, loss of PAN deadenylase activity leads to arrest in M phase, defective spindles, and increased cell death. PAN consists of the catalytic subunit Pan2 and the RNA binding subunit Pan3. Consistent with a role in mitosis,PAN2interacts genetically with tubulin genes, prefoldin complex genes and the mitotic cyclinCLB1.PAN2knockdown in human cultured cells disrupts mitosis and results in spindle fragmentation leading to abnormal cell division, while expression of humanPAN2in yeast rescuespan2Δ cell-cycle phenotypes. Hence, we reveal an important highly conserved role for PAN in ensuring proper mitosis when cells are under microtubule stress. We propose PAN regulates PATLs of mRNAs of key cell-cycle/mitotic proteins in response to defective spindles.Author SummaryProper cell division is essential for the growth and survival of all living organisms. Our study investigates the role of PAN deadenylase complex in yeast and human cultured cells under microtubule stress, induced by microtubule inhibitors used in cancer treatment. The PAN complex, consisting of Pan2 and Pan3, trims the poly(A) tails of mRNAs. We found that loss of PAN activity leads to cell cycle arrest in M-phase, spindle defects and increased cell death in yeast. Similarly,PAN2knockdown in human cultured cells disrupts mitosis and causes abnormal cell division, indicating a conserved function across species. We propose that PAN regulates mRNA poly(A) tail lengths of key mitotic proteins to ensure proper mitosis under stress. This regulation likely prevents faulty spindle formation by repressing translation of these mRNAs. Interestingly, PAN’s role is specific to stress conditions, as cells without PAN function normally otherwise. Our findings highlight PAN’s critical role in maintaining genomic stability and proper cell division during microtubule stress, providing insights into the post-transcriptional regulation of cell cycle and potential targets for cancer therapy.