Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1.

Human Molecular Genetics
Gabriel BalmusRobert S Weiss

Abstract

The human genomic instability syndrome ataxia telangiectasia (A-T), caused by mutations in the gene encoding the DNA damage checkpoint kinase ATM, is characterized by multisystem defects including neurodegeneration, immunodeficiency and increased cancer predisposition. ATM is central to a pathway that responds to double-strand DNA breaks, whereas the related kinase ATR leads a parallel signaling cascade that is activated by replication stress. To dissect the physiological relationship between the ATM and ATR pathways, we generated mice defective for both. Because complete ATR pathway inactivation causes embryonic lethality, we weakened the ATR mechanism to different degrees by impairing HUS1, a member of the 911 complex that is required for efficient ATR signaling. Notably, simultaneous ATM and HUS1 defects caused synthetic lethality. Atm/Hus1 double-mutant embryos showed widespread apoptosis and died mid-gestationally. Despite the underlying DNA damage checkpoint defects, increased DNA damage signaling was observed, as evidenced by H2AX phosphorylation and p53 accumulation. A less severe Hus1 defect together with Atm loss resulted in partial embryonic lethality, with the surviving double-mutant mice showing synergistic increas...Continue Reading

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Citations

Apr 29, 2015·Oncogene·G BalmusR S Weiss
Mar 25, 2014·Current Opinion in Genetics & Development·Gabriel Balmus, Rebecca E McIntyre
Jan 9, 2014·Radiation Research·Constantinos G Broustas, Howard B Lieberman
Sep 10, 2013·Cell Cycle·Amy M LyndakerHoward B Lieberman
Jan 1, 2015·Nature Protocols·Gabriel BalmusRebecca E McIntyre
Apr 11, 2020·Genetics·Vera D RinaldiJohn C Schimenti
May 7, 2021·Genetics·Vera D RinaldiJohn C Schimenti

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