title: Two S-phase checkpoint systems, one involving the function of both BIME and Tyr15 phosphorylation of p34cdc2, inhibit NIMA and prevent premature mitosis.
abstract: We demonstrate that there are at least two S-phase checkpoint mechanisms controlling mitosis in Aspergillus. The first responds to the rate of DNA replication and inhibits mitosis via tyrosine phosphorylation of p34cdc2. Cells unable to tyrosine phosphorylate p34cdc2 are therefore viable but are unable to tolerate low levels of hydroxyurea and prematurely enter lethal mitosis when S-phase is slowed. However, if the NIMA mitosis-promoting kinase is inactivated then non-tyrosine-phosphorylated p34cdc2 cannot promote cells prematurely into mitosis. Lack of tyrosine-phosphorylated p34cdc2 also cannot promote mitosis, or lethality, if DNA replication is arrested, demonstrating the presence of a second S-phase checkpoint mechanism over mitotic initiation which we show involves the function of BIME. In order to overcome the S-phase arrest checkpoint over mitosis it is necessary both to prevent tyrosine phosphorylation of p34cdc2 and also to inactivate BIME. Lack of tyrosine phosphorylation of p34cdc2 allows precocious expression of NIMA during S-phase arrest, and lack of BIME then allows activation of this prematurely expressed NIMA by phosphorylation. The mitosis-promoting NIMA kinase is thus a target for S-phase checkpoint controls.
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, PA 17822-2617, USA.
authors.forename: X S
authors.initials: XS
authors.lastname: Ye
authors.forename: R R
authors.initials: RR
authors.lastname: Fincher
authors.forename: A
authors.initials: A
authors.lastname: Tang
authors.forename: K
authors.initials: K
authors.lastname: O'Donnell
authors.forename: S A
authors.initials: SA
authors.lastname: Osmani
mesh_terms: D001233:Aspergillus nidulans / Q000166:cytology* / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018797:Cell Cycle Proteins; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D017931:DNA Primers; D005656:Fungal Proteins / Q000502:physiology*; D006918:Hydroxyurea / Q000494:pharmacology; D008938:Mitosis; D008969:Molecular Sequence Data; D009154:Mutation; D000072380:NIMA-Related Kinase 1; D000072379:NIMA-Related Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
chemical_list: C065697:BIME protein, Emericella nidulans; D018797:Cell Cycle Proteins; D017931:DNA Primers; D005656:Fungal Proteins; D014443:Tyrosine; D004247:DNA; D000072380:NIMA-Related Kinase 1; D000072379:NIMA-Related Kinases; C442331:NIMA-related kinase 6; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D006918:Hydroxyurea