Intrinsic genomic instability from naturally occurring DNA structures: An introduction to the special issue

We have accumulated a great amount of information about different types of DNA damage that are mutagenic and carcinogenic, and how they challenge the DNA repair systems in living cells. The connections between unrepaired or improperly repaired DNA damage and carcinogenesis are well documented. However, there are significant sources of genomic instability in addition to those due to DNA alterations caused by environmental genotoxic agents, endogenous sources of DNA damage, and the intrinsic chemical instability of DNA molecules. There are potential threats to genomic stability from noncanonical DNA structures that can form within the naturally occurring DNA sequences found in living cells. Nearly a dozen well-characterized types of non-B DNA structures can form in a sequence-specific fashion in the genome. Among these sequences are inverted repeats, which can adopt hairpin and cruciform structures; mirror repeats, which have the potential to form intramolecular triplexes or H-DNA; alternating purine– pyrimidine repeats, which can form left-handed Z-DNA; guanine-rich repeats, which have the capacity to adopt G-4 quadruplexes in certain sequence contexts; and triplet repeat sequences, which can adopt a variety of structures in a sequence-specific fashion such as slipped DNA and sticky DNA (similar to two interacting triplex structures). Sequences with the potential to adopt these noncanonical DNA structures occur with surprisingly high frequency in the human genome; for example, potential Z-DNA-forming sequences appear roughly every 3000 nucleotides and an H-DNA-forming sequence can be found about every 50 000 nucleotides. Some types of noncanonical structures such as G-4 quadruplexes can be formed in abundance in telomeres or in the immunoglobulin genes, in which they appear to be important for the generation of billions of different antibodies. Furthermore, there are documented hot spots for genomic instability and predisposition tocancer that occur within or near DNA sequences that can adopt non B-form DNA secondary structures. Only recently has it been realized that non-B DNA structures, such as the H-DNA-forming sequence in the human c-myc gene, can induce genetic instability in mammalian cells. Non-B-forming sequences have also been shown to induce DNA double-strand breaks in mammalian cells, supporting a role for DNA structure in oncogenic translocations and cancer etiology. These noncanonical DNA structures may serve important regulatory functions, but additionally they can be the source of genomic instability, particularly as such instability may lead to cancer, aging, and human genetic diseases. We are on the crest of a wave of new discoveries in this exciting field in which there are many opportunities for translational research. It is therefore timely to consider the relative roles that such non-B-form structures might play in DNA metabolism and human disease. That was our rationale for generating this special issue of Molecular Carcinogenesis, to explore the natures of the various sorts of noncanonical DNA structures and their effects upon cellular functions such as replication and transcription, as well as to learn their roles in genomic instability through deleterious recombinational exchange and chromosomal alterations. While covering many examples, this special issue is not meant to be comprehensive in this emerging field, but rather it is intended to raise awareness and interest in considering these structures along with other sources of genomic instability in studies of human disease and carcinogenesis. While some nucleotide sequences were excluded through evolution because they have resulted in deleterious secondary DNA structures, others may have been retained as important recognition elements, with regulatory roles in genomic structure and gene expression. In that case it becomes a ‘‘trade off,’’ in which the need for the regulatory role MOLECULAR CARCINOGENESIS 48:271–272 (2009)