Meeting DNA palindromes head-to-head

Abstract

Particular DNA sequences have long been known to have exceptional structures and biological properties. Famous in the medical world are the trinucleotide repeat sequences, such as (CTG)(n), and their association with more than a dozen neurodegenerative diseases. Numerous meetings have been held to discuss these repeats and the diseases they cause. Now, a much-needed meeting has been held to discuss other noncanonical (non-B-form) DNA structures, their properties, and their biological consequences. Although the meeting was titled "DNA palindromes: roles, consequences, and implications of structurally ambivalent DNA," the participants discussed and debated a range of additional structures-dubbed "Z," "HJ," "G4," and "H" DNA-as well as trinucleotide repeats. These remarkable structures can have profound effects on chromosomes and organisms, ranging from mutational hotspots in bacteria to causes of intellectual disability in humans. Bringing together four dozen researchers prominent in the field focused attention on these controversial DNA structures in a way that promises to spur greater understanding of DNA elements critical to life and health.

Figure 1.

Noncanonical DNA structures. Canonical B-form DNA (center, boxed) is a right-handed double helix. DNA with special nucleotide sequences can adopt other structures, many of which were discussed at the FASEB meeting reported here. Additional structures are in Figure 4. Figure courtesy of Richard Sinden.

Figure 2.

Alternative conformations of DNA at the junctions of arms in cruciforms and HJs. In the center panel, the four arms are splayed apart into a square, forming a roughly planar structure. On the left, arms A and D are coaxially stacked to form a nearly continuous duplex, and arms B and C are similarly stacked. Note that the two DNA strands indicated by black lines (denoted “continuous”) are each in one stack, whereas the gray strands (denoted “discontinuous”) span different stacks. On the right, arms A and B are in one stack, and the gray strands are continuous. Figure courtesy of David Lilley.

Figure 3.

Two models of palindrome-mediated gross chromosomal rearrangement. (Left) A palindrome extrudes into a cruciform, which is cleaved by an HJ resolvase. The resultant nicks are ligated to form large hairpins. Replication of a hairpin can produce a giant (chromosome-size) palindrome. (Right) A DSB near a palindrome leads, by unwinding or degradation, to ssDNA, which can fold into a large hairpin and be converted into a giant palindrome as on the left. Other rearrangements of the large hairpin can give translocations or other gross chromosomal rearrangements. Figure courtesy of David Leach.

Figure 4.

G4 DNA structures. (A, left) Hydrogen bonding of four guanine bases (guanine quartet or G4). (Center) Three possible inter- and intrastrand pairings of G4. (Right) Two polymorphic structures that may be formed by G₃N₃G₃N₂G₄ N₂G₅. Each plane segment is a G4. (B) Formation of intrastrand G4 structures during replication (left) or transcription (right). Figure courtesy of Nancy Maizels.