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J. Biol. Chem., Vol. 277, Issue 34, 31005-31013, August 23, 2002
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From the Molecular Virology Section, Laboratory of Molecular
Microbiology, NIAID, National Institutes of Health,
Bethesda, Maryland 20892-0460
In eukaryotes, the mitotic spindle assembly
checkpoint provides a monitor for the fidelity of chromosomal
segregation. In this context, the mitotic arrest deficiency protein 2 (MAD2) censors chromosomal mis-segregation by monitoring microtubule
attachment/tension, a role that requires its attachment to
kinetochores. Studies in yeast have shown that binding of MAD1 to MAD2
is important for the checkpoint function of the latter. The
interactions between human MAD1 (hsMAD1) and human MAD2 (hsMAD2)
have, however, remained poorly characterized. Here we report that two
leucine zipper domains (amino acids 501-522 and 557-571) in hsMAD1
are required for its contact with hsMAD2. Interestingly, in several
cancer cell lines, we noted the frequent presence of a coding single
nucleotide Arg to His polymorphism at codon 558 located within the
second leucine zipper of hsMAD1. We found that hsMAD1H558 is less
proficient than hsMAD1R558 in binding hsMAD2 and in enforcing mitotic
arrest. We also document a first example of loss-of-heterozygosity for a spindle checkpoint gene (at the hsMAD1 558 locus) in a
human breast cancer. Based on our findings, it is possible that
hsMAD1H558 could be an at-risk polymorphism that contributes to
attenuated spindle checkpoint function in human cells.
Characterization of Regions in hsMAD1 Needed for
Binding hsMAD2
A POLYMORPHIC CHANGE IN AN hsMAD1 LEUCINE ZIPPER AFFECTS
MAD1-MAD2 INTERACTION AND SPINDLE CHECKPOINT FUNCTION*
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Bldg. 4, Rm. 306, 9000 Rockville Pike, Bethesda, MD 20892-0460. Tel: 301-496-6680; Fax:
301-480-3686; E-mail: kj7e@nih.gov.
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