ATM, mutation of which leads to the human autosomal recessive disorder Ataxia-
Telangiectasia (A-T), plays a critical role in maintaining genetic stability and preventing
cancer formation. ATM is a PI-3 like kinase that functions as a sensor and signal
transducer in DNA damage responses. Currently, most of the functional studies of ATM
focus on its essential role in the cellular response to ionizing radiation-induced DNA double
strand breaks. However, because of the complexity of A-T phenotypes and many of the A-T
phenotypes can not be simply explained by the lack of an optimal DNA damage response,
functions of ATM in the absence of DNA damage must be further examined. We have
found that ATM was required for the activation of the spindle checkpoint, a process that
protects against chromosome missegregation by delaying sister chromatid separation. Our
preliminary data demonstrated that ATM was activated during mitosis in the absence of
DNA damage. The mitosis-dependent activation of ATM requires functional Aurora-B.
Furthermore we found that Aurora-B phosphorylated ATM at Ser1403 both in vitro and in
vivo. In depth studies have found that Aurora-B associated with ATM during mitosis and
ATM was required for the activity of Bub1. Further we found that ATM phosphorylated Bub1
(at Ser314) and Mad 1(at Ser214). Our general hypothesis in this proposal is that mitotic
activation of ATM is governed by Aurora-B and has functional significance in regulation of
the spindle checkpoint. Therefore we propose to study the mechanisms of mitotic activation
of ATM and to dissect the ATM pathways in the spindle checkpoint. Three specific aims are
proposed. Aim 1 will focus on investigate the molecular mechanism of the ATM activation.
Aim 2 will study the role of ATM Ser1403 phosphorylation on mitotic progression and the
spindle checkpoint. Aim 3 will focus on studying the functional significance of mitotic-
dependent ATM phosphorylation of its downstream target. Our long-term goal of this
project is to better understand the role of ATM in mitotic cell cycle control as a basis for
providing insights into general mechanisms of carcinogenesis, cell growth and cell death.
Dissecting the important role of ATM in mitosis may help understand many A-T phenotypes
and find a cure for the disease.