Control of G1 arrest after DNA damage.

Abstract

The temporal relationship between DNA damage and DNA replication may be critical in determining whether the genetic changes necessary for cellular transformation occur after DNA damage. Recent characterization of the mechanisms responsible for alterations in cellcycle progression after DNA damage in our laboratory have implicated the p53 (tumor suppressor) protein in the G, arrest that occurs after certain types of DNA damage. In particular, we found that levels of p53 protein increased rapidly and transiently after nonlethal doses of y irradiation (XRT) in hematopoietic cells with wild-type, but not mutant, p53 genes. These changes in p53 protein levels were temporally linked to a transient GI arrest in these cells. Hematopoietic cells with mutant or absent p53 genes did not exhibit this G, arrest, through they continued to demonstrate a G2 arrest. We recently extended these observations of a tight correlation between the status of the endogenous p53 genes and this G, arrest after XRT and this cell-cycle alteration after XRT was then established by transfecting cells lacking endogenous p53 genes with a wild-type gene and observing acquisition of the G1 arrest and by transfecting cells processing endogenous wild-type p53 genes with a mutant p53 gene and observing loss of the GI arrest after XRT. These observations and their significance for our understanding of the mechanisms of DNA damage-induced cellular transformation are discussed.Transient alterations in cell-cycle progression after DNA damage are well documented. Presumably, these responses permit optimal repair of damage before the cell reinitiates replicative DNA synthesis (G1 arrest) and/or begins mitosis (G2 arrest). If replicative DNA synthesis or mitosis occurred before repair of the damage, then mutagenic lesions could be "fixed" and propagated (1) and could contribute to the progressive increase in genomic changes necessary for neoplastic transformation (Fig. 1). Currently, little is known about the cellular signals required for these cell-cycle check points after DNA damage in mammalian cells. In yeast, the RAD9 gene product appears to be necessary for G2 arrest after damage (2), but the factors required for G1 arrest remain unclear.We recently began to characterize some of the mechanisms that control cell-cycle changes in response to DNA damage in mammalian cells (3). Using hematopoietic cell lines as models, we found that nonlethal doses of y irradiation (XRT) transiently inhibit replicative DNA synthesis via both G1 and G2 arrests. We reasoned that this inhibition of replicative DNA syn- ' thesis after XRT could result from either inhibition of a positive regulator of DNA synthesis or stimulation or a negative regulator. Because the p53 gene product had been demonstrated to be a negative regulator of DNA synthesis (4-7) and because this tumor-suppressor gene is the most commonly mutated gene thus far identified in human cancers, linkage of p53 to this DNA damage-induced inhibition of DNA replication was an attractive possibility.Because the wil...

Loss of G 1 /S Checkpoint in Human Immunodeficiency Virus Type 1-Infected Cells Is Associated with a Lack of Cyclin-Dependent Kinase Inhibitor p21/Waf1

“…Gamma irradiation has been one of the best-studied agents for inducing DNA damage in a variety of eukaryotic systems, ranging from yeast to humans, and its consequential effects on various pathways have been well characterized. These pathways, including evolutionarily conserved Chk1, ATR, and nuclear poly(ADP-ribose) polymerase and nonconserved p21, p53 and AbI, guard genomic integrity after DNA damage (21,30,34,47).…”

Molecular mechanisms ofH. pyloriassociated gastric carcinogenesis

“…The activated p53 protein can affect the expression of a number of genes, including the cyclin-dependent kinase inhibitor (CKI) p21, which regulates G1 cell cycle check point and bax, a gene involved in apoptosis. Therefore, the protein can either prevent the cell from entering the S phase until the DNA damage is repaired and/or can turn on the apoptotic pathways to destroy an abnormal cell [33] . The p53 gene abnormalities in gastric cancer are usually point mutations or allelic deletions leading to over-expression of the protein, loss of p53 function and with resulting defects in the protective pathways of cell cycle arrest and apoptosis.…”

Assessment of candidate immunohistochemical prognostic markers of meningioma recurrence

“…p53 can be activated by DNA damage, oxidative stress, osmotic shock, ribonucleotide depletion or oncogene expression. The activation is marked by an increase in the half-life of p53 and a change of its conformation [16], therefore shows increased Labelling Index (LI) with immunohistochemistry with the polyclonal anti bodies routinely used in tumour diagnostics. The anticancer activity of p53 is through several mechanisms: it activates DNA repair proteins, induces growth arrest at the G1/S regulation point through p21 or initiates apoptosis if the DNA damage is irreversible [12].…”