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

Abstract

The 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, but their potential roles in regulation of cell-cycle mRNA PATLs has not been investigated. 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, PAN2 interacts genetically with tubulin genes, prefoldin complex genes and the cyclins CLB1 and CLN3. PAN2 knockdown in human cultured cells disrupts mitosis and results in spindle fragmentation leading to abnormal cell division, while expression of human PAN2 in yeast rescues pan2Δ 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.