DNA Accessibility: A Determinant of Mammalian Cell Differentiation?

Abstract

Rats bearing intracerebral 9L tumors were whole-brain irradiated with 1250 to 5000 rad, and the in situ DNA repair kinetics of the undifferentiated tumor cells and terminally differentiated cerebellar neurons were examined by alkaline sucrose gradient sedimentation in zonal rotors with gradient reorienting capability. Biphasic repair kinetics were observed for both tumor cells and cerebellar neurons. Quantitation and analysis of the slow phase of the repair process suggest that the dividing tumor cell genome is completely accessible to the enzymatic repair machinery, while it is possible that the genome of the permanently nondividing neuron may contain a region that is inaccessible to this repair machinery.

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

“…This could be important because it is known that differentiation increases radiosensitivity in human carcinoma cells under both hypoxic and aerobic conditions (Hallows et al, 1988;Hoffmann et al, 1999). Radiosensitisation might be due to inhibited DNA repair arising from the limited access of DNA repair machinery in differentiated cells (Wheeler and Wierowski, 1983). To the extent that the in vitro results apply clinically, hypoxic cells that are more differentiated might be less radioresistant than otherwise thought.…”

Influence of novobiocin on <FONT FACE=Symbol>g</font>-irradiation G0-lymphocytes as analyzed by cytogenetic endpoints

“…However, the cell response to chemical and/or physical agents may be influenced by several factors, such as cell line or organism, drug concentration or dose, protocol of cell treatment, etc. It is well known that the firm compactation of chromatin may impair the accessibility of DNA repair enzymes to the damaged sites, since variations in chromatin conformation and organization can affect the extent of DNA damage and repair (Wheeler and Wierowski, 1983;Yasui et al, 1987). Chiu et al (1986) showed that chromatin structure plays an important role in the formation and repair of DNA lesions in Chinese hamster cells exposed to γ-irradiation.…”

Radiation and Diabetic Retinopathy: A Dark Synergy

“…We suggested that unrepaired DNA damage may trigger cell death if ECs harboring such damage were forced to re-enter the cell cycle, in order to cover defects created by loss of adjacent cells within the EC monolayer [6,21]. Although the influence of chromatin conformation on mechanisms of DNA repair were largely unknown in the early 1990s, previous studies by Wheeler and Wierowski showed that DNA damage was more efficiently repaired in dividing tumor cells than in terminally differentiated CNS neurons [177]. These authors concluded that the difference in DNA repair efficiency was due to easier access of the repair enzymes to lesion sites in dividing cells [177].…”

“…Although the influence of chromatin conformation on mechanisms of DNA repair were largely unknown in the early 1990s, previous studies by Wheeler and Wierowski showed that DNA damage was more efficiently repaired in dividing tumor cells than in terminally differentiated CNS neurons [177]. These authors concluded that the difference in DNA repair efficiency was due to easier access of the repair enzymes to lesion sites in dividing cells [177]. Although their "Accessibility Hypothesis" did not embrace chromatin accessibility [177], the concept prompted our consideration of the need for bulky enzymes to penetrate a crowded macromolecular environment to access DNA break sites, and condensed chromatin as a potential barrier to the repair apparatus, as compared to the open conformation of euchromatin [6,21].…”