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Meeting DNA Palindromes Head-To-Head Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press MEETING REVIEW Meeting DNA palindromes head-to-head Gerald R. Smith1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA Particular DNA sequences have long been known to held at Saxtons River, VT, July 6–11, 2008. The struc- have exceptional structures and biological properties. tures discussed included palindromes, Holliday junc- Famous in the medical world are the trinucleotide repeat tions (HJs), G4 DNA, Z DNA, and trinucleotide repeats sequences, such as (CTG)n, and their association with in organisms as diverse as poxvirus, bacteria, yeasts, more than a dozen neurodegenerative diseases. Numer- Drosophila, mice, and humans. One was left with the ous meetings have been held to discuss these repeats and feeling that “standard” (i.e., B-form) linear DNA is inert the diseases they cause. Now, a much-needed meeting relative to the dynamic structures discussed, and that has been held to discuss other noncanonical (non-B-form) these alternative structures deserve their own meeting, DNA structures, their properties, and their biological which, it was agreed, should be continued on a biennial consequences. Although the meeting was titled “DNA basis. palindromes: roles, consequences, and implications of structurally ambivalent DNA,” the participants dis- cussed and debated a range of additional structures— DNA palindromes and inverted repeats—sliding dubbed “Z,” “HJ,” “G4,” and “H” DNA—as well as tri- into cruciforms and hairpins nucleotide repeats. These remarkable structures can have profound effects on chromosomes and organisms, A palindrome, such as the famous “A man, a plan, a ranging from mutational hotspots in bacteria to causes of canal, Panama,” reads the same in both directions. In the intellectual disability in humans. Bringing together four DNA and RNA worlds the term means that one strand Ј → Ј dozen researchers prominent in the field focused atten- reads the same in the 5 3 direction as the comple- Ј → Ј tion on these controversial DNA structures in a way that mentary strand reads in the 5 3 direction. An ex- Ј Ј promises to spur greater understanding of DNA elements ample is 5 -GTTAG|CTAAC-3 , where | indicates the critical to life and health. center of the palindrome. If sufficiently long, these se- quences can extrude to form a cruciform, with a few unpaired nucleotides at the center flanked by dsDNA Usually thought of as a linear double helix, DNA can in (Fig. 1). When present in ssDNA, such as during replica- reality assume many different structures, some of which tion or transcription, the palindrome can fold into a hair- have profound influences on DNA’s biological functions. pin, equivalent to half of a cruciform. In both cases the For example, palindromic DNA sequences, which read capped end is a substrate for two known classes of en- the same in opposite directions (but on different strands), zymes: (1) the MRN complex of eukaryotes, and its ar- can extrude to form a cruciform, with both strands in- cheal equivalent MR and bacterial equivalent SbcCD; volved, or a hairpin, with only one strand involved (Fig. and (2) Artemis of vertebrates, involved in cutting hair- 1). These structures are acted upon by enzymes that have pins made by the RAG complex during V(D)J recombi- only slight activity on linear double-helical DNA. There nation, which produces active immunoglobulin genes. is extensive evidence that these and other noncanonical [MRN derives from Mre11, Rad50, and Nbs1, the poly- DNA structures can have dire consequences such as ini- peptides in the human complex; the Saccharomyces cer- tiating chromosomal translocations, which can result in evisiae homolog of Nbs1 is Xrs2, and the Schizosaccha- cancer or developmental defects. Only recently was a romyces pombe homolog of Mre11 is Rad32. MRN is meeting held with emphasis on noncanonical DNA struc- used here for all species. Escherichia coli SbcC and SbcD tures other than trinucleotide repeats. Organized by David are homologs of Rad50 and Mre11.] Leach (University of Edinburgh), Susanna Lewis (Univer- Closely related to a palindrome is an inverted repeat sity of Toronto), and Alison Rattray (National Cancer (IR), in which there are additional, unique base pairs at Institute), this meeting was sponsored by FASEB and the center (| in the example above). In this case, pairing between the repeats leaves extensive single-stranded loops of the unique base pairs at the tips of the cruciform [Keywords: DNA palindromes; G4 DNA; chromosomal rearrangements; (Fig. 1). The energetic cost to form this structure with cruciforms; noncanoncal DNA structures; trinucleotide repeats] single-stranded loops is large in dsDNA but not in 1Correspondence. E-MAIL [email protected]; FAX (206) 667-6497. ssDNA. Craig Benham (University of California at Davis) Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1724708. discussed the energetics of formation of hairpins and cru- 2612 GENES & DEVELOPMENT 22:2612–2620 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Meeting DNA palindromes head-to-head Figure 1. Noncanonical DNA structures. Canonical B-form DNA (center, boxed) is a right-handed double helix. DNA with spe- cial nucleotide sequences can adopt other structures, many of which were discussed at the FASEB meeting reported here. Ad- ditional structures are in Figure 4. Figure courtesy of Richard Sinden. ciforms, which indicate that even imperfect repeats can The frequency of the Chr. 11:22 translocation is so form these structures under the right conditions. In high—approximately 2 × 10−5 per DNA molecule—that many cases IRs can have as profound effects as palin- it can be detected by PCR of sperm or testis biopsies. dromes, presumably by folding during replication when Assay of highly diluted samples shows that the two re- the DNA is partly single-stranded. ciprocal translocation types occur in a single sperm, sup- One of the most dramatic examples of palindromes porting the view that the palindromes on each chromo- causing human disease was presented by Beverly some are cut at about the same time, and the ends are Emanuel (University of Pennsylvania) and Hiroki Kura- swapped and rejoined. These translocations are not de- hashi (Fujita Health University). Palindromes of ∼500 tectable by PCR in lymphoblasts or fibroblasts, and thus base pairs (bp) or greater on human chromosomes 11 and appear to be germline-specific, but the basis of this speci- 22 are the sites of the most frequent recurrent human ficity is unclear. Emanuel noted, however, that the rel- translocation (other than Robertsonian translocations evant points on Chrs. 11 and 22 are closer to each other between centromeres). Carriers of the Chr. 11:22 recip- in meiotic cells than in mitotic cells and closer than rocal translocation are asymptomatic except for reduced other chromosome pairs. Kurahashi suggested that the fertility, but their chromosomally unbalanced progeny translocation occurs after meiotic replication, when the suffer from severe developmental defects, including in- chromosomes become highly compacted for packaging tellectual disability and cardiac defects. The hotspots for into sperm heads. Consistent with this view, the three these translocations contain AT-rich palindromes at analyzed cases of the translocation arising de novo oc- each chromosomal break point. Designated PATRR for curred in the father of the translocation carrier. palindromic AT-rich regions, the repeats on Chr. 11 are Although the molecular basis of these debilitating 99% identical to each other but share no significant ho- translocations is clearly palindromic DNA, the mecha- mology with the PATRR on Chr. 22. The break points of nism by which palindromes react has been most thor- the translocations are all located within 20 bp of the oughly studied in model organisms, especially bacteria centers of the PATRRs. A few nucleotides are lost during and yeasts. Half of the talks at this conference dealt translocation, suggesting that nonhomologous end-join- with microbes. Multiple strong parallels suggest that ing is involved. Presumably, at each palindrome a cruci- the mechanisms deduced in microbes readily pertain to form is cut diagonally to make a stable hairpin, or a multicellular species, including humans. hairpin is formed in ssDNA (see Fig. 3, below). A cut at David Lilley (Dundee University) led off the confer- each hairpin tip yields uncapped dsDNA ends, which ence with a description of the structure and branch mi- after loss of a few nucleotides are joined to form the gration of cruciforms and closely related HJs discussed translocation. below. The four arms of both junctions are arranged in a Support for this mechanism comes from studies of “stacked X” form, in which the arms are in two pairs of plasmids with insertions of the PATRRs and variants of coaxially aligned, stacked helices with an angle of ∼60° them. Such plasmids readily adopt the cruciform struc- between the axes (Fig. 2). The choice of partners in this ture, and stability of the cruciform directly correlates coaxial alignment depends on the nucleotides at the base with the rate of plasmid fusion at the PATRRs when of the junction (and to a lesser degree the next base pairs). introduced into human cells. Furthermore, the PATRR During branch migration, the arms must lose their co- on Chr. 11 is polymorphic, and shorter PATRRs, which axial stacking to adopt an open square form (Fig. 2). This presumably form less stable cruciforms, translocate less open form is more stable in the absence of Mg2+ ions, frequently. which counter the repulsive negative charges of the GENES & DEVELOPMENT 2613 Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Smith the structure of HJs in solution and their branch migra- tion with much greater resolution—at the level of indi- vidual base pairs.
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