Abstract
Sequences that can adopt alternative DNA structures (i.e., non-B DNA) are very abundant in mammalian genomes, and recent studies have revealed many important biological functions of non-B DNA structures in chromatin remodeling, DNA replication, transcription, and genetic instability. Here, we provide results from an in silico web-based search engine coupled with cell-based experiments to characterize the roles of non-B DNA conformations in genetic instability in eukaryotes. The purpose of this article is to illustrate strategies that can be used to identify and interrogate the biological roles of non-B DNA structures, particularly on genetic instability. We have included unpublished data using a short H-DNA-forming sequence from the human c-MYC promoter region as an example, and identified two different mechanisms of H-DNA-induced genetic instability in yeast and mammalian cells: a DNA replication-related model of mutagenesis; and a replication-independent cleavage model. Further, we identified candidate proteins involved in H-DNA-induced genetic instability by using a yeast genetic screen. A combination of in silico and cellular methods, as described here, should provide further insight into the contributions of non-B DNA structures in biological functions, genetic evolution, and disease development.
Highlights
Our understanding of the structure and function of genomic DNA has been dramatically advanced in the past few decades
In addition to the regulatory functions of non-coding RNAs such as microRNAs that are transcribed from these “junk DNA” sequences (Perera and Ray, 2012; Hausser and Zavolan, 2014), many repetitive sequences are involved in chromosome architecture and organization and gene expression regulation due to their ability to adopt DNA conformations that differ from the canonical B-form DNA
More than 15 types of alternative non-B DNA structures have been described to date (Choi and Majima, 2011; Wang and Vasquez, 2014); for example, simple repeats can form small “loop-out” bubbles caused by the misalignment of the repeat units (Mirkin, 2007), trinucleotide repeats can form imperfect hairpin structures, and inverted repeat sequences have the potential to adopt perfect self-complementary hairpins and cruciforms (Sinden et al, 1991; Voineagu et al, 2008; Lu et al, 2015)
Summary
Our understanding of the structure and function of genomic DNA has been dramatically advanced in the past few decades. In addition to the regulatory functions of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) that are transcribed from these “junk DNA” sequences (Perera and Ray, 2012; Hausser and Zavolan, 2014), many repetitive sequences are involved in chromosome architecture and organization and gene expression regulation due to their ability to adopt DNA conformations that differ from the canonical B-form DNA (i.e., non-B DNA). Intramolecular triplex structures (HDNA) can form at mirror-repeat homopurine/homopyrimidine sequences via formation of Hoogsteen hydrogen bonding of the purine-rich strand through the major groove of the underlying duplex (Voloshin et al, 1988; Frank-Kamenetskii and Mirkin, 1995). Because four guanine bases can associate through Hoogsteen-hydrogen bonding to form a square planar structure (guanine tetrad), four guanine-rich regions (from the same DNA molecule or different molecules) that contain runs of three or more guanines can stack to form G-quadruplex or G4 DNA structures (Lane et al, 2008; Bochman et al, 2012)
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