Mad1

Mad1 is a non-essential protein in yeast which has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homolog’s of Mad1 are conserved in eukaryotes from yeast to mammals.

Introduction

In the early 90s, yeast genes were identified which mutations resulted in a defect in mitotic arrest in response to microtubule disassembly (mitotic arrest deficient genes - MAD genes). This cells showed during division no mitotic arrest in the presence of microtubule polymerization inhibitors and were therefore not able to delay cell division. The genes identified included the MAD1, MAD2 and MAD3 genes. They are conserved in all eukaryotes and are involved in a pathway that is active in prometaphase to prevent the premature separation of sister chromatids and constitute the so-called spindle assembly checkpoint(SAC). This checkpoint monitors the status of chromosome attachment to the mitotic spindle and inhibits the metaphase to anaphase transition by preventing the activation of the anaphase-promoting complex/cyclosome (APC/C), and thereby the degradation of cell cycle regulators. Mad1 is in this pathway accumulated at unattached kinetochores and acts as a sensor for unattached kinetochores in this machinery.