Scopul nostru este sprijinirea şi promovarea cercetării ştiinţifice şi facilitarea comunicării între cercetătorii români din întreaga lume.
Autori: Balmus G, Zhu M, Mukherjee S, Lyndaker AM, Hume KR, Lee J, Riccio ML, Reeves AP, Sutter N, Noden DM, Peters RM, Weiss RS.
Editorial: Human Molecular Genetics, 21, 2012.
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, while 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 increases in genomic instability and specific developmental defects including dwarfism, craniofacial abnormalities, and brachymesophalangy, phenotypes that are observed in several human genomic instability disorders. In addition to identifying tissue-specific consequences of checkpoint dysfunction, these data highlight a robust, cooperative configuration for the mammalian DNA damage response network and further suggest HUS1 and related genes in the ATR pathway as candidate modifiers of disease severity in A-T patients.
Cuvinte cheie: Hus1, Atm, Atr, checkpoint, developmenta