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Gene Review

MAD1  -  Mad1p

Saccharomyces cerevisiae S288c

Synonyms: Mitotic arrest deficient protein 1, Spindle assembly checkpoint component MAD1, YGL086W
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Disease relevance of MAD1

  • We show that the association between Mad1 and mSin3 is not only dependent on the helical SID but is also dependent on both putative helices of the mSin3 PAH2 region, suggesting that stable interaction requires all three helices [1].

High impact information on MAD1


Biological context of MAD1

  • We have cloned the MAD1 gene and show that when it is disrupted yeast cells have the same phenotype as the previously isolated mad1 mutants: they fail to delay the metaphase to anaphase transition in response to microtubule depolymerization [7].
  • Deletion of MAD1 or MAD2 did not affect steady-state nucleocytoplasmic distribution of a classical nuclear localization signal-containing reporter, a nuclear export signal-containing reporter, or Ran localization [8].
  • Mad1p becomes hyperphosphorylated when wild-type cells are arrested in mitosis by benomyl treatment, or by placing a cold sensitive tubulin mutant at the restrictive temperature [7].
  • We discuss the possible functions of Mad1p at this cell cycle checkpoint [7].
  • We conclude that Mad1 and Mad2 are required to detect bipolar orientation and/or tension at kinetochores, whereas Mad3 is not [9].

Anatomical context of MAD1


Associations of MAD1 with chemical compounds


Physical interactions of MAD1

  • On the basis of these results and genetic analysis of double mutants, we propose a model in which Mad1p bound to a Nup53p-containing complex sequesters Mad2p at the NPC until its release by activation of the spindle checkpoint [11].
  • Mouse homologs of SIN3 have been identified through screens for proteins interacting with the mammalian Mad1 protein, a transcriptional repressor [12].

Enzymatic interactions of MAD1

  • In addition, Mad2p binds to all of the different phosphorylated isoforms of Mad1p that can be resolved on SDS-PAGE [13].

Regulatory relationships of MAD1

  • Here, we show that budding yeast Mad1p has a regulated association with Bub1p and Bub3p during a normal cell cycle and that this complex is found at significantly higher levels once the spindle checkpoint is activated [14].

Other interactions of MAD1

  • In budding yeast, the Mad1, 2, 3, and Bub1, 2, 3 proteins mediate this arrest [15].
  • Checkpoint arrest in the absence of bipolar orientation and tension (induced by replication block in a cdc6 mutant) was lacking in cells without MAD1 or MAD2 [9].
  • In budding yeast, Mad1, Mad2, and Mad3 proteins are equally required for arrest in the presence of damage induced by antimicrotubule drugs or catastrophic loss of spindle structure [9].
  • Unlike cells delayed in mitosis by spindle damage or MPS1 kinase overexpression, hyperphosphorylated forms of the Mad1p checkpoint protein did not accumulate [16].
  • Mutation of this motif abolishes checkpoint function, indicating that formation of the Mad1p-Bub1p-Bub3p complex is a crucial step in the spindle checkpoint mechanism [14].

Analytical, diagnostic and therapeutic context of MAD1


  1. Mad proteins contain a dominant transcription repression domain. Ayer, D.E., Laherty, C.D., Lawrence, Q.A., Armstrong, A.P., Eisenman, R.N. Mol. Cell. Biol. (1996) [Pubmed]
  2. Feedback control of mitosis in budding yeast. Li, R., Murray, A.W. Cell (1991) [Pubmed]
  3. Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores. Chen, R.H., Waters, J.C., Salmon, E.D., Murray, A.W. Science (1996) [Pubmed]
  4. Mitotic chromosome condensation in the rDNA requires TRF4 and DNA topoisomerase I in Saccharomyces cerevisiae. Castaño, I.B., Brzoska, P.M., Sadoff, B.U., Chen, H., Christman, M.F. Genes Dev. (1996) [Pubmed]
  5. Spindle checkpoint proteins and chromosome-microtubule attachment in budding yeast. Gillett, E.S., Espelin, C.W., Sorger, P.K. J. Cell Biol. (2004) [Pubmed]
  6. BubR1 is essential for kinetochore localization of other spindle checkpoint proteins and its phosphorylation requires Mad1. Chen, R.H. J. Cell Biol. (2002) [Pubmed]
  7. Mad1p, a phosphoprotein component of the spindle assembly checkpoint in budding yeast. Hardwick, K.G., Murray, A.W. J. Cell Biol. (1995) [Pubmed]
  8. Ran GTPase regulates Mad2 localization to the nuclear pore complex. Quimby, B.B., Arnaoutov, A., Dasso, M. Eukaryotic Cell (2005) [Pubmed]
  9. Bipolar orientation of chromosomes in Saccharomyces cerevisiae is monitored by Mad1 and Mad2, but not by Mad3. Lee, M.S., Spencer, F.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Interactions between Mad1p and the nuclear transport machinery in the yeast Saccharomyces cerevisiae. Scott, R.J., Lusk, C.P., Dilworth, D.J., Aitchison, J.D., Wozniak, R.W. Mol. Biol. Cell (2005) [Pubmed]
  11. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. Iouk, T., Kerscher, O., Scott, R.J., Basrai, M.A., Wozniak, R.W. J. Cell Biol. (2002) [Pubmed]
  12. SIN3-dependent transcriptional repression by interaction with the Mad1 DNA-binding protein. Kasten, M.M., Ayer, D.E., Stillman, D.J. Mol. Cell. Biol. (1996) [Pubmed]
  13. The spindle checkpoint of budding yeast depends on a tight complex between the Mad1 and Mad2 proteins. Chen, R.H., Brady, D.M., Smith, D., Murray, A.W., Hardwick, K.G. Mol. Biol. Cell (1999) [Pubmed]
  14. Complex formation between Mad1p, Bub1p and Bub3p is crucial for spindle checkpoint function. Brady, D.M., Hardwick, K.G. Curr. Biol. (2000) [Pubmed]
  15. Budding yeast Bub2 is localized at spindle pole bodies and activates the mitotic checkpoint via a different pathway from Mad2. Fraschini, R., Formenti, E., Lucchini, G., Piatti, S. J. Cell Biol. (1999) [Pubmed]
  16. Bub1p kinase activates the Saccharomyces cerevisiae spindle assembly checkpoint. Farr, K.A., Hoyt, M.A. Mol. Cell. Biol. (1998) [Pubmed]
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