Chk2 protects against radiation-induced genomic instability.
The murine Chk2 kinase is activated after exposure to ionizing radiation and is necessary for p53-dependent apoptosis, but the role Chk2 plays in determining genomic stability is poorly understood. By analyzing the sensitivity of Chk2-deficient murine and human cells to a range of DNA-damaging agents, we show that Chk2 deficiency results in resistance to agents that generate double-strand breaks but not to other forms of damage. Surprisingly, the absence of Chk2 results in increased sensitivity to UV-radiation-induced DNA damage. Defective apoptosis after radiation-induced DNA damage may result in genomic instability; therefore, the consequences of Chk2 deficiency on genomic instability were assayed using an in vitro screen. Gene amplification was not detected in untreated Chk2(-/-) cells, but the rate of gene amplification after irradiation was elevated and was similar to that found in p53 compromised cells. A synergistic increase in genomic instability was seen after disruption of both Chk2 and p53 function, indicating that the two proteins have non-redundant roles in regulating genome stability after irradiation. The data demonstrate that Chk2 functions to maintain genome integrity after radiation-induced damage and has important implications for the use of Chk2 inhibitors as adjuvant cancer therapy.
MacLaren
Ann
A
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Slavin
Daniela
D
McGowan
Clare H
CH
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002460:Cell Line; D064447:Checkpoint Kinase 2; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005784:Gene Amplification / Q000528:radiation effects; D042822:Genomic Instability / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D011836:Radiation Tolerance / Q000528:radiation effects; D014466:Ultraviolet Rays
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases