DNA damage and cell cycle checkpoints

Abstract

DNA is prone to numerous forms of damage that can injure cells and impair fitness. Cells have evolved an array of mechanisms to repair these injuries. Proliferating cells are especially vulnerable to DNA damage due to the added demands of cellular growth and division. Cell cycle checkpoints represent integral components of DNA repair that coordinate cooperation between the machinery of the cell cycle and several biochemical pathways that respond to damage and restore DNA structure. By delaying progression through the cell cycle, checkpoints provide more time for repair before the critical phases of DNA replication, when the genome is replicated, and of mitosis, when the genome is segregated. Loss or attenuation of checkpoint function may increase spontaneous and induced gene mutations and chromosomal aberrations by reducing the efficiency of DNA repair. Defects in checkpoint control have been seen in certain hereditary cancer syndromes and at early stages of cell transformation. Mutations in checkpoint control genes therefore may contribute to the genetic instability that appears to drive neoplastic evolution.

Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light

“…HMEC 184 and 184B5 surpassed sham-irradiated levels by 4 h post-irradiation, with 184A1 showing a 70% recovery. Dose-response analyses were conducted at 2 h post-irradiation, a time when inhibition of mitosis is maximal (Kaufmann et al, 1995). A dose of 0.5 Gy yielded an 80 ± 97% decrease in the mitotic fraction in the cell lines examined (data not shown).…”

“…Quantitation of G2 delay G2 delay was analysed by quantitating the mitotic fraction as previously described (Kaufmann et al, 1995). Brie¯y, exponentially growing cells were irradiated with 0 ± 2 Gy of ionizing radiation and returned to the incubator.…”

Evidence for the inactivation of multiple replicative lifespan genes in immortal human squamous cell carcinoma keratinocytes

“…There is persuasive evidence from the induction of immortality in human ®broblasts that cellular immortality involves the abrogation of both the p53 and RB-1 tumor suppressor gene pathways (Shay et al, 1991;Hara et al, 1991) and decreased regulation of the cell cycle in both G 1 and G 2 (Kaufmann et al, 1995). Although these events are necessary to induce immortality (Wright et al, 1989;Radna et al, 1989) they are still insu cient and a further genetic alteration which activates telomerase (Counter et al, 1992(Counter et al, , 1994) is usually essential.…”

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

“…Human and rodent cells immortalized by a thermolabile T construct cease to proliferate at the nonpermissive temperature, arresting with an increased G2 cell population (Jat and Sharp, 1989; Radna et al, 1989;Mignotte et al, 1990). In addition, recent work by Kaufmann et al (1995) has shown that precrisis human ®broblasts that express T antigen display a reduced mitotic delay following DNA damage. It was unclear, however, whether this e ect was a direct consequence of T antigen expression or was a phenotype acquired during the extended proliferation of genetically unstable T antigen-expressing cell clones.…”