PubMed · 14755268
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Ronald T Hay. 2004. Modifying NEMO.. https://doi.org/10.1038/ncb0204-89
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Bacteria encounter acid stress under a variety of circumstances. Acid stress induces DNA damage and genomic instability, most directly via acid-catalyzed depurination reactions that generate apurinic (abasic, AP) sites on the deoxyribose phosphate backbone. DNA damage responses are important in bacterial resistance to acids. A recent report provided evidence that a DNA repair glycosylase, AlkX, which is capable of initiating the repair of interstrand DNA cross-links (ICLs), contributes to acid resistance by the pulmonary pathogen Acinetobacter baumannii (Kunkle et al. Proc. Nat. Acad. Sci. USA, 2024, 121, e2402422121). This suggested the possibility that AP-derived ICLs might contribute to the acid stress in bacteria. This idea is predicated on earlier work showing that AP sites can generate ICLs via reactions of the ring-opened AP aldehyde with the exocyclic amino groups of nucleobases on the opposing strand of duplex DNA (Price, N. E. J. Am. Chem. Soc. 2014, 136, 3483). However, it was not clear from previous work whether AP-derived ICLs could be generated under conditions of acid stress. The results reported here provide evidence for ICL formation under conditions of acid stress via a sequential process involving acid-catalyzed depurination followed by cross-linking of the resulting AP site with an adenine residue on the opposing strand of duplex DNA. This supports the possibility that AP-derived interstrand cross-links could contribute to the effects of acid stress in bacteria, and proteins involved in the repair of these lesions could be involved in resistance to acid stress.
The formamidopyrimidines Fapy.dA and Fapy.dG are produced in DNA as a result of oxidative stress. These lesions readily epimerize in water, an unusual property for nucleosides. The equilibrium mixture slightly favors the beta-anomer, but the configurational status in DNA is unknown. The ability of endonuclease IV (Endo IV) to efficiently incise alpha-deoxyadenosine was used as a tool to determine the configuration of Fapy.dA and Fapy.dG in DNA. Endo IV incision of the C-nucleoside analogues of Fapy.dA was used to establish selectivity for the alpha-anomer. Incision of alpha-C-Fapy.dA follows Michaelis-Menten kinetics (K(m) = 144.0 +/- 7.5 nM, k(cat) = 0.58 +/- 0.21 min(-1)), but the beta-isomer is a poor substrate. Fapy.dA incision is considerably slower than that of alpha-C-Fapy.dA, and does not proceed to completion. Endo IV incision of Fapy.dA proceeds further upon rehybridization, suggesting that the lesion reequilibrates and that the enzyme preferentially cleaves duplex DNA containing alpha-Fapy.dA. The extent of Fapy.dA incision suggests that the lesion exists predominantly ( approximately 90%) as the beta-anomer in DNA. Endo IV incises Fapy.dG to less than 5% under comparable reaction conditions, suggesting that the lesion exists almost exclusively as its beta-anomer in DNA.
Nuclear export of mRNA is a central step in gene expression that shows extensive coupling to transcription and transcript processing. However, little is known about the fate of mRNA and its export under conditions that damage the DNA template and RNA itself. Here we report the discovery of four new factors required for mRNA export through a screen of all annotated nonessential Saccharomyces cerevisiae genes. Two of these factors, mRNA surveillance factor Rrp6 and DNA repair protein Lrp1, are nuclear exosome components that physically interact with one another. We find that Lrp1 mediates specific mRNA degradation upon DNA-damaging UV irradiation as well as general mRNA degradation. Lrp1 requires Rrp6 for genomic localization to genes encoding its mRNA targets, and Rrp6 genomic localization in turn correlates with transcription. Further, Rrp6 and Lrp1 are both required for repair of UV-induced DNA damage. These results demonstrate coupling of mRNA surveillance to mRNA export and suggest specificity of the RNA surveillance machinery for different transcript populations. Broadly, these findings link DNA and RNA surveillance to mRNA export.