Disease relevance of Atr

• We have characterized the human and mouse counterpart of the Schizosaccharomyces pombe Rad3 protein, named Atr (for ataxia-telangiectasia- and rad3-related), and the protein that is mutated in ataxia-telangiectasia, Atm [1].

High impact information on Atr

• Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint [2].
• Overexpression of wild-type Atr enhances, whereas overexpression of the kinase-defective mutant Atr inhibits S345 phosphorylation of Chk1 induced by UV treatment [2].
• Atr is found at sites along unpaired or asynapsed chromosomal axes, whereas Atm is found along synapsed chromosomal axes [1].
• The Atr and Atm protein kinases associate with different sites along meiotically pairing chromosomes [1].
• More detailed analysis of specific cells in seminiferous tubules shows localization of Atr to the nuclei of cells in the process of meiosis I [1].

Biological context of Atr

• This is the first demonstration of a nuclear association of Atr and Atm proteins with meiotic chromosomes and suggests a direct role for these proteins in recognizing and responding to DNA strand interruptions that occur during meiotic recombination [1].
• The Atm and Atr proteins are mitotic cell-cycle proteins that also associate with chromatin during meiotic prophase I [3].
• Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome [4].
• We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation [4].
• Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation [4].

Analytical, diagnostic and therapeutic context of Atr

• Using immunoprecipitation and immunoblot analysis, we show that Atr and Atm proteins are approximately 300 and 350 kD relative molecular mass, respectively, and further demonstrate that both proteins have associated protein kinase activity [1].

References