Problems and paradigms: Fine tuning of DNA repair in transcribed genes: Mechanisms, prevalence and consequences

Abstract

Cells fine-tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV-induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair-defective diseases may involve repair-transcription coupling: three candidate genes have been suggested. However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription. Repair of other damage departs further from the paradigm, even in some UV-mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV-induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted.

Nucleotide distribution in gymnosperm nuclear sequences suggests a model for GC-content change in land-plant nuclear genomes

“…Under this model it is suggested (1) that a GC-error-prone DNA repair mechanism may be active in the vicinity of transcribed regions and could therefore be responsible for GC enrichment in biased genes, (2) that in dicots this repair mechanism, if present, is not GC-error prone, and (3) that this mechanism for the introduction of GC bias into plant genes operates independently from CpG suppression, which lowers GC content. This simple but speculative model can account for observed nucleotide patterns in plant genomes and is supported by recent findings (Bootsma and Hoeijmakers 1993;Downes et al 1993;Selby and Sancar 1993;Schaeffer et al 1993) which demonstrate the presence of transcriptionally coupled DNA repair systems in eukaryotes.…”

“…We offer no explanation for the variation in efficiency of "GC-error-prone repair" machinery across genes within a biased genome (Table 3) other than the postulate that some genes may lose their affinity as substrates for error-prone repair synthesis. Indeed, in animals there is no simple correlation between rates of transcription and repair synthesis, and the relationship between chromatin structure and rate of repair synthesis for active genes is also unclear (Downes et al 1993). Kojima et al (1992); maize GapC1, Martinez et al (1989); maize GapA1, QuigIey et al (1988); maize ~GapA1, Quigley et aI, (1989).…”

The RAD7 and RAD16 genes, which are essential for pyrimidine dimer removal from the silent mating type loci, are also required for repair of the nontranscribed strand of an active gene in Saccharomyces cerevisiae.

“…For UV-induced cyclobutane pyrimidine dimers, this differential repair has been described for organisms ranging from Escherichia coli to humans (3,5,13,17,18,33,34,38,39). Efficient repair of transcribed strands of active genes is thought to contribute to increased survival of the cells as a result of fast recovery of RNA synthesis that is otherwise blocked by UV damage.…”

DNA repair systems

“…For comparison, healthy human cells would normally a empt to repair all instances of damage, regardless of whether it is located in the transcribed or in the non-transcribed genomic regions. The ra o of the efficiency of repair of the transcribed strand versus the non-transcribed strand of transcribed genes may also show significant differences between the different species -up to 10 in rodents, 5 in yeast and as low as 2 in humans [1397]. Presumably, check-ups of the integrity of the whole genome are carried out in rodent cells only as part of the rou ne prepara ons before DNA replica on, as it has been reported that cells of rapidly prolifera ng rodent ssues (e.g.…”