Working together and apart: the twisted relationship of the Mre11 complex and Chk2 in apoptosis and tumor suppression.
Central to the DNA damage response (DDR) is the highly conserved Mre11 complex consisting of Mre11, Rad50 and Nbs1. The Mre11 complex acts as a sensor of DNA double-strand breaks (DSBs) and regulates the signal transduction cascades that are triggered following damage detection.(1) Rare human genetic instability syndromes such as Ataxia-telangiectasia (A-T) and Nijmegen Breakage Syndrome (NBS) have underscored the importance of the DSB response in the suppression of tumorigenesis, as well as other severe pathologies affecting the development of both the immune system and the central nervous system. Using murine models of the human diseases, we have investigated the role of the Mre11 complex, and other modulators of the DSB response, in tumor suppression.(2,3) We found that the checkpoint kinase Chk2 is crucial for the suppression of a diverse array of tumor types in Mre11 complex mutants and uncovered multiple roles for the Mre11 complex in apoptotic signaling in parallel to Chk2.(4,5).
Stracker
Travis H
TH
Molecular Biology, Sloan-Kettering Institute, New York, New York 10021, USA.
Petrini
John H J
JH
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases