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Abstract

Cells induce the expression of DNA-repair enzymes, activate cell-cycle checkpoints and, under some circumstances, undergo apoptosis in response to DNA-damaging agents. The mechanisms by which these cellular responses are triggered are not well understood, but there is recent evidence that the transcription machinery might be used in DNA-damage surveillance and in triggering DNA-damage responses to suppress mutagenesis. Transcription might also act as a DNA-damage dosimeter where the severity of blockage determines whether or not to induce cell death. Could transcription therefore be a potential therapeutic target for anticancer strategies?

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Cancer. p53, guardian of the genome.

D P Lane (1992)

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Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.

Carlos P. Rubbi, Jo Milner (2003)

p53 protects against cancer through its capacity to induce cell cycle arrest or apoptosis under a large variety of cellular stresses. It is not known how such diversity of signals can be integrated by a single molecule. However, the literature reveals that a common denominator in all p53-inducing stresses is nucleolar disruption. We thus postulated that the impairment of nucleolar function might stabilize p53 by preventing its degradation. Using micropore irradiation, we demonstrate that large amounts of nuclear DNA damage fail to stabilize p53 unless the nucleolus is also disrupted. Forcing nucleolar disruption by anti-upstream binding factor (UBF) microinjection (in the absence of DNA damage) also causes p53 stabilization. We propose that the nucleolus is a stress sensor responsible for maintenance of low levels of p53, which are automatically elevated as soon as nucleolar function is impaired in response to stress. Our model integrates all known p53-inducing agents and also explains cell cycle-related variations in p53 levels which correlate with established phases of nucleolar assembly/disassembly through the cell cycle.

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Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene.

P Hanawalt, J Spivak, I Mellon (1987)

We find a dramatic difference in the efficiency of removal of UV-induced pyrimidine dimers from the transcribed and nontranscribed strands of the dihydrofolate reductase (DHFR) gene in cultured hamster and human cells. In hamster cells, 80% of the dimers are removed from the transcribed strand in 4 hr, but little repair occurs in the nontranscribed strand even after 24 hr. In human cells, repair is significantly faster in the transcribed strand than in the other strand. Furthermore, in the 5' flanking region of the human DHFR gene, selective rapid repair occurs in the opposite DNA strand relative to the transcribed strand of the DHFR gene. This strand is thought to serve as a template for transcription of a divergent transcript. These results have important implications for excision repair pathways and mutagenesis in mammalian cells.

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PubMed ID:: 15343279

DOI:: 10.1038/nrc1435

ScienceOpen disciplines: Chemistry

Keywords: Aging,physiology,Apoptosis,Cell Cycle,DNA Damage,DNA Repair,Humans,Mutation,Neoplasms,genetics,physiopathology,Transcription, Genetic

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ScienceOpen disciplines: Chemistry

Keywords: Aging, physiology, Apoptosis, Cell Cycle, DNA Damage, DNA Repair, Humans, Mutation, Neoplasms, genetics, physiopathology, Transcription, Genetic

Transcription - guarding the genome by sensing DNA damage.

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Abstract

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Genome Integrity

Most cited references 115

Cancer. p53, guardian of the genome.

Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.

Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene.

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