Originally published as Genetics Published Articles Ahead of Print on March 31, 2005.

Genetics, Vol. 170, 509-517, June 2005, Copyright © 2005
doi:10.1534/genetics.105.041426

The C-Terminal Half of Saccharomyces cerevisiae Mad1p Mediates Spindle Checkpoint Function, Chromosome Transmission Fidelity and CEN Association

James P. Kastenmayer^*,1, Marina S. Lee^,1, Andrew L. Hong^*,1, Forrest A. Spencer and Munira A. Basrai^*,2

^* Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20889
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

² Corresponding author: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, National Naval Medial Center, Bldg. 8, Room 5101, 8901 Wisconsin Ave., Bethesda, MD 20889.
E-mail: basraim{at}nih.gov

The evolutionarily conserved spindle checkpoint is a key mechanism ensuring high-fidelity chromosome transmission. The checkpoint monitors attachment between kinetochores and mitotic spindles and the tension between sister kinetochores. In the absence of proper attachment or tension, the spindle checkpoint mediates cell cycle arrest prior to anaphase. Saccharomyces cerevisiae Mad1p is required for the spindle checkpoint and for chromosome transmission fidelity. Moreover, Mad1p associates with the nuclear pore complex (NPC) and is enriched at kinetochores upon checkpoint activation. Using partial mad1 deletion alleles we determined that the C-terminal half of Mad1p is necessary and sufficient for checkpoint activation in response to microtubule depolymerizing agents, high-fidelity transmission of a reporter chromosome fragment, and in vivo association with centromeres, but not for robust NPC association. Thus, spindle checkpoint activation and chromosome transmission fidelity correlate and these Mad1p functions likely involve kinetochore association but not robust NPC association. These studies are the basis for elucidating the role of protein complexes containing Mad1p in the spindle checkpoint pathway and in maintaining genome stability in S. cerevisiae and other systems.

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