DNA damage checkpoints in mammals

Abstract

DNA damage is a common event and probably leads to mutation or deletion within chromosomal DNA, which may cause cancer or premature aging. DNA damage induces several cellular responses including DNA repair, checkpoint activity and the triggering of apoptotic pathways. DNA damage checkpoints are associated with biochemical pathways that end delay or arrest of cell-cycle progression. These checkpoints engage damage sensor proteins, such as the Rad9-Rad1-Hus1 (9-1-1) complex, and the Rad17-RFC complex, in the detection of DNA damage and transduction of signals to ATM, ATR, Chk1 and Chk2 kinases. Chk1 and Chk2 kinases regulate Cdc25, Wee1 and p53 that ultimately inactivate cyclin-dependent kinases (Cdks) which inhibit cell-cycle progression. In this review, we discuss the molecular mechanisms by which DNA damage is recognized by sensor proteins and signals are transmitted to Cdks. We classify the genes involved in checkpoint signaling into four categories, namely sensors, mediators, transducers and effectors, although their proteins have the broad activity, and thus this classification is for convenience and is not definitive.

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…ATM has been reported as a key sensor in response to DNA double strand breaks (Lavin, 2007;Lavin and Kozlov, 2007;Niida and Nakanishi, 2006) or DNA ends (Bolderson et al, 2004).…”

Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

“…Chk2 was shown to synergize with other genes or factors that perpetuate DNA damage repair during G2/M phase rather than inducing G2/M phase arrest (Hirao et al 2000). Active Chk2 is known to phosphorylate ser-216 (negative regulatory site) of Cdc25C protein phosphatase, leading in turn to the inhibition of Cdc2 kinase and consequently G2/M blockade (Kastan and Bartek 2004;Niida and Nakanishi 2005). These findings are consistent with our results that only genistein has an effect on cell cycle through the down-regulation of Cyclin B1 and Chk2 in intestinal Caco-2 cells.…”

High expression of DNA repair pathways is associated with metastasis in melanoma patients

“…A second subgroup of overexpressed mRNA in M þ melanomas includes the components of the clamp-loader RAD17-RFC2-5 (RAD17, RFC2, 4 and 5) as well as of the clamp RAD9-RAD1-HUS1 (HUS1). Both complexes are coordinately involved in DNA replication fork stall and rescue, recombination, NER and telomere maintenance (Niida and Nakanishi, 2006). A third subgroup of overexpressed genes in M þ melanomas includes the mRNA's coding for CHK1 and CHK2, two major protein kinases activated by ATM/ATR kinases to transduce signals induced by fork stalling, DNA DSB, DNA ICL or telomere abnormalities.…”