Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA strands of actively transcribed genes. Human hereditary diseases that present a deficiency only in TCR are characterized by sunlight sensitivity without enhanced skin cancer. Although multiple gene products are implicated in TCR, we still lack an understanding of the precise signals that can trigger this pathway. Futile cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease.

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The SNF2 family of proteins includes representatives from a variety of species with roles in cellular processes such as transcriptional regulation (e.g. MOT1, SNF2 and BRM), maintenance of chromosome stability during mitosis (e.g. lodestar) and various aspects of processing of DNA damage, including nucleotide excision repair (e.g. RAD16 and ERCC6), recombinational pathways (e.g. RAD54) and post-replication daughter strand gap repair (e.g. RAD5). This family also includes many proteins with no known function. To better characterize this family of proteins we have used molecular phylogenetic techniques to infer evolutionary relationships among the family members. We have divided the SNF2 family into multiple subfamilies, each of which represents what we propose to be a functionally and evolutionarily distinct group. We have then used the subfamily structure to predict the functions of some of the uncharacterized proteins in the SNF2 family. We discuss possible implications of this evolutionary analysis on the general properties and evolution of the SNF2 family.

Mutational processes constantly shape the somatic genome, leading to immunity, aging, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional (“T-class”) asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations, and replicative (“R-class”) asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of Transcription-Coupled Damage (TCD) on the non-transcribed DNA strand, and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.

In human cells, efficient global genomic repair of DNA damage induced by ultraviolet radiation requires the p53 tumor suppressor, but the mechanism has been unclear. The p48 gene is required for expression of an ultraviolet radiation-damaged DNA binding activity and is disrupted by mutations in the subset of xeroderma pigmentosum group E cells that lack this activity. Here, we show that p48 mRNA levels strongly depend on basal p53 expression and increase further after DNA damage in a p53-dependent manner. Furthermore, like p53 ؊͞؊ cells, xeroderma pigmentosum group E cells are deficient in global genomic repair. These results identify p48 as the link between p53 and the nucleotide excision repair apparatus.

The ability to recognize and repair abnormal DNA structures is common to all forms of life. Studies in a variety of species have identified an incredible diversity of DNA repair pathways. Documenting and characterizing the similarities and differences in repair between species has important value for understanding the origin and evolution of repair pathways as Ž well as for improving our understanding of phenotypes affected by repair e.g., mutation rates, lifespan, tumorigenesis, . survival in extreme environments . Unfortunately, while repair processes have been studied in quite a few species, the ecological and evolutionary diversity of such studies has been limited. Complete genome sequences can provide potential sources of new information about repair in different species. In this paper, we present a global comparative analysis of DNA repair proteins and processes based upon the analysis of available complete genome sequences. We use a new form of analysis that combines genome sequence information and phylogenetic studies into a composite analysis we refer to as phylogenomics. We use this phylogenomic analysis to study the evolution of repair proteins and processes and to predict the repair phenotypes of those species for which we now know the complete genome sequence. q 1999 Elsevier Science B.V. All rights reserved.

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Nucleotide excision repair helps to ameliorate the lethal and mutagenic consequences of DNA damage by removing helix-distorting lesions from cellular genomes. We have previously analysed the removal of ultraviolet-induced cyclobutane pyrimidine dimers from specific DNA sequences in mammalian cells and demonstrated that transcriptionally active genes are preferentially repaired. Additionally, we found that in rodent and human cells only the transcribed strand of the dihydrofolate reductase gene is selectively repaired. Transcription is blocked by pyrimidine dimers in template DNA and the selective removal of these lesions seems to be important for cell survival after irradiation with ultraviolet light. To determine whether this feature of repair is common to prokaryotes and eukaryotes and better to understand its mechanism, we have investigated repair in the two separate DNA strands of the lactose operon of ultraviolet-irradiated Escherichia coli. We find a dramatic difference in the repair of the two strands only when transcription is induced. Most dimers are removed from the transcribed strand of the induced operon within five minutes of irradiation. In the nontranscribed strand, repair is significantly slower and resembles that found in both strands of the uninduced operon. Thus there seems to be a mechanism that couples nucleotide excision repair and transcription.