Effects of inhibitors of DNA synthesis and protein synthesis on the rate of DNA synthesis after exposure of mammalian cells to ultraviolet light

Griffiths, Tony; Dahle, Dan; Meechan, Paul J.; Carpenter, J. G.

doi:10.1016/0005-2787(81)90026-5

Cited by 9 publications

(5 citation statements)

References 20 publications

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“…This aspect can be exemplified by the following question: Is a faster degradation of a clock element, such as Per2 , leading to a shortening or lengthening of the period? Degradation rates are intimately related to the effective delay [65], [83], [84] and consequently one might expect that faster degradation leads to a shorter delay and, subsequently, to a shorter period. This is indeed observed in a cellular model of the FASPS disorder [20].…”

Section: Resultsmentioning

confidence: 99%

Tuning the Mammalian Circadian Clock: Robust Synergy of Two Loops

et al. 2011

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The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period - a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations.

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Section: Resultsmentioning

confidence: 99%

Tuning the Mammalian Circadian Clock: Robust Synergy of Two Loops

et al. 2011

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“…The data of Gupta and Sirover (1980) that indicated an increase in excision repair occurred prior to DNA synthesis in normal human fibroblasts suggest that a cell cycle specific increase in a non-excision repair or recovery system is possible. The data from experiments using an inhibitor of DNA synthesis, hydroxyurea (HU) (Clarkson and Mitchell, 1979;Griffiths et al, 1981), complicate this model since these results demonstrated no measurable increase in survival or recovery of DNA synthesis after holding Chinese hamster cells in HU for 2.5 or 5 h for asynchronous cells. It is possible, however, that the post-irradiation treatment with HU might have blocked any recovery (Waltersetal., 1976;Djordjevic andTolmach, 1967).…”

Section: Discussionmentioning

confidence: 99%

“…Painter (1978Painter ( ,1980 repeated D'Ambrosio's experiments on asynchronous V-79 cells and found that the results were totally consistent with a model that allowed replication up to the first lesion, bypass of a fraction of the blocks during the incubation between exposures and subsequent re-blockage after the second irradiation. The results of Griffiths et al (1981) andGautschi etal. (1973), suggested that the inhibition of recovery due to incubation in cycloheximide could be fully accounted for by its inhibition of DNA replication and not its effects on protein synthesis.…”

Section: Introductionmentioning

confidence: 97%

“…Several models have been proposed to explain why the rate of DNA synthesis recovers to control levels without excision of all the DNA lesions. There is a large body of data from a variety of techniques that suggests that the recovery of DNA synthesis is intimately connected with DNA replication (progression through S phase) (Domon and Rauth, 1973;Todd, 1973;Clarkson and Mitchell, 1979;Griffiths et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

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Recovery of Subchromosomal Dna Synthesis in Synchronous V‐79 Chinese Hamster Cells After Ultraviolet Light Exposure

Meechan

Carpenter

Griffiths

1986

Photochem & Photobiology

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Abstract— Previous work obtained from Chinese hamster V‐79 cells indicated that, immediately following exposure, UV‐induced lesions acted as blocks to elongation of nascent strands, but gradually lost that ability over a 10 h period after exposure to 10 J/m2. The work reported herein attempted to examine possible cell cycle mediated alterations in the recovery of DNA synthesis. Kinetic incorporation of radiolabeled thymidine studies indicated that there may have been a more rapid recovery of DNA synthesis in cells irradiated in G1 or G2vs cells irradiated in S phase. DNA fiber autoradiograms prepared from synchronous cells indicated that after irradiation in any phase of the cell cycle, the length of newly synthesized DNA was equal to control lengths 1 h after exposure to 5.0 J/m2 (or 1 h after entering S phase for cells irradiated in G1 or G2). This observed recovery was not solely due to an excision process. No cell cycle mediated difference in the number of dimers induced or removed as a function of cell cycle position was observed. These results appear to be consistent with a continuum of effects, with initiation effects dominating the response at low fluences, gapped synthesis at intermediate fluences and elongation inhibition at high fluences. The fluences at which each event dominates may be cell‐line specific.

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“…There is no new evidence concerning chromosomal mutations that would support the notion of a requirement for inducible processes for mutation fixation or for recovery of DNA synthesis. Our previous arguments against the use of cycloheximide as a protein synthesis inhibitor, on the ground that it is also a good inhibitor of DNA synthesis [Stone-Wolff and Rossman, 19811, are supported by the results of Griffiths et al [1981]. These workers used concentrations of cycloheximide and hydroxyurea that inhibited DNA synthesis in V79 cells by 70%, but inhibited protein synthesis by 95% and 0%, respectively.…”

Section: Mutagenesis Of Chromosomal Genes In Mammalian Cellsmentioning

confidence: 95%