Effects of Replication and Transcription on DNA Structure-Related Genetic Instability

Guliang Wang, Karen Vasquez
2017 Genes  
Many repetitive sequences in the human genome can adopt conformations that differ from the canonical B-DNA double helix (i.e., non-B DNA), and can impact important biological processes such as DNA replication, transcription, recombination, telomere maintenance, viral integration, transposome activation, DNA damage and repair. Thus, non-B DNA-forming sequences have been implicated in genetic instability and disease development. In this article, we discuss the interactions of non-B DNA with the
more » ... plication and/or transcription machinery, particularly in disease states (e.g., tumors) that can lead to an abnormal cellular environment, and how such interactions may alter DNA replication and transcription, leading to potential conflicts at non-B DNA regions, and eventually result in genetic stability and human disease. The Human Genome Project revealed that >50% of human genomic DNA consists of repetitive sequences, containing repeating units of different lengths ranging from single base-pairs to large segments of DNA at a mega base-pair (Mbp) scale [12] . These repetitive elements were originally considered as "by-products" of genome evolution or locations of viral attack and were often referred to as "junk DNA". However, we have now realized that these repetitive elements play important regulatory roles in genomic structure and function. Notably, many of these repeats are able to form alternative secondary DNA conformations that differ from the classic B-DNA structure, due to interand intra-molecular interactions within/between the repetitive elements. Figure 1 depicts several commonly studied non-B DNA conformations. More than 15 types of "non-B" DNA structures that differ from B-DNA have been characterized to date [6, 13, 14] . For most types of non-B DNA structures, the first step of the conformational transition from B-form DNA to non-B is separation of the DNA duplex into single-stranded DNA (ssDNA), providing the single-stranded repetitive sequence the opportunity to interact with nucleotides that are on the same strand or with those of the underlying duplex regions. For example, a single-stranded inverted repeat sequence can form Watson-Crick base-pairs between the self-complementary regions on the same strand to form hairpin or cruciform structures [15] ; an H-DNA structure can form at a purine-or pyrimidine-rich ssDNA region with mirror repeat symmetry that can fold back and Hoogsteen hydrogen bond to the major groove of the other half of the duplex containing mirror symmetry [16, 17] . If the ssDNA contains four guanine runs, each containing three or more guanines, the ssDNA can fold into a G-tetrad structure via Hoogsteen-hydrogen bonding to form a square planar structure [18] , and three or more of such stacked guanine tetrads are referred to as G-quadruplex or G4 DNA structures [19, 20] . ssDNA containing simple repetitive units can re-anneal with the complementary strand with misalignment, resulting in loop structures [21] . Z-DNA is a left-handed helix that can form in regions of alternating purine-pyrimidine sequences, where the guanines in every two base-pairs are in the syn conformation, in contrast to the canonical anti-conformation in B-DNA, which twists the phosphodiester backbone into a zigzag (hence the name) pattern [22, 23] . A-DNA is a duplex structure that exits under dehydrating conditions such as crystal formation, with altered major and minor groove structures [6] .
doi:10.3390/genes8010017 pmid:28067787 pmcid:PMC5295012 fatcat:pu35wsk72nacrf66blw7ibozle