Cruciform DNA

Cruciform DNA is a form of non-B DNA that requires at least a 6 nucleotide sequence of inverted repeats to form a structure consisting of a stem, branch point and loop in the shape of a cruciform, stabilized by negative DNA supercoiling.[1] Two classes of cruciform DNA have been described; folded and unfolded. Folded cruciform structures are characterized by the formation of acute angles between adjacent arms and main strand DNA. Unfolded cruciform structures have square planar geometry and 4-fold symmetry in which the two arms of the cruciform are perpendicular to each other.[1]The formation of cruciform structures in linear DNA is thermodynamically unfavorable due to the possibility of base unstacking at junction points and open regions at loops.[1] Cruciform DNA is found in both prokaryotes and eukaryotes and has a role in the transcription of DNA,[2] double strand repair, DNA translocation and recombination. Cruciform structures can increase genomic instability and are involved in the formation of various diseases, such as cancer.[3]

Biological significance

Cruciform DNA structures are stabilized through supercoiling and their formation alleviates stress generated from DNA supercoiling. Cruciform structures block the recognition of the tet promoter in pX by RNA polymerase. The cruciform structures can also disrupt a step in the kinetic pathway, shown when gyrase is inhibited by novobiocin. Cruciform structures regulate transcription initiation[2] such as the suppression of pX transcription. DNA replication can then be inhibited by cruciform containing tertiary structures of DNA formed during recombination,[4] which can be studied to help treat malignancy. Recombination is also observed in Holliday junctions, a type of cruciform structure.

RuvA / RuvB repair

In bacterial plasmids, RuvA and RuvB repair DNA damage, and are involved in the recombination process of Holliday junctions.[4] These proteins are also responsible for regulating branch migration. During branch migration, the RuvAB complex helps to initiate recombination when it binds and unzips the Holliday junction, like DNA helicase, and also when the RuvAB/Holliday junction complex is cleaved, once RuvC binds to it.

p53 binding to cruciform forming targets

Another example of cruciform structure significance is seen in the interaction between p53, a tumor suppressor, and cruciform forming sequences. p53 binding correlates with inverted repeat sequences, such as the ones that help form cruciform DNA structures. Under negative superhelical stress p53 binds preferentially to cruciform forming targets due to the A/T rich environment which feature these necessary inverted repeat sequences.[5]

References
  1. Shlyakhtenko LS, Potaman VN, Sinden RR, Lyubchenko YL (July 1998). "Structure and dynamics of supercoil-stabilized DNA cruciforms". J. Mol. Biol. 280 (1): 61–72. CiteSeerX 10.1.1.555.4352. doi:10.1006/jmbi.1998.1855. PMID 9653031.
  2. Horwitz MS, Loeb LA (August 1988). "An E. coli promoter that regulates transcription by DNA superhelix-induced cruciform extrusion". Science. 241 (4866): 703–5. doi:10.1126/science.2456617. PMID 2456617.
  3. Štros, Michal; Muselíková-Polanská, Eva; Pospíšilová, Šárka; Strauss, François (2004-06-01). "High-Affinity Binding of Tumor-Suppressor Protein p53 and HMGB1 to Hemicatenated DNA Loops". Biochemistry. 43 (22): 7215–7225. doi:10.1021/bi049928k. ISSN 0006-2960. PMID 15170359.
  4. Shiba T, Iwasaki H, Nakata A, Shinagawa H (October 1991). "SOS-inducible DNA repair proteins, RuvA and RuvB, of Escherichia coli: functional interactions between RuvA and RuvB for ATP hydrolysis and renaturation of the cruciform structure in supercoiled DNA". Proc. Natl. Acad. Sci. U.S.A. 88 (19): 8445–9. doi:10.1073/pnas.88.19.8445. PMC 52525. PMID 1833759.
  5. Jagelská, Eva B.; Brázda, Václav; Pečinka, Petr; Paleček, Emil; Fojta, Miroslav (2008-05-15). "DNA topology influences p53 sequence-specific DNA binding through structural transitions within the target sites". Biochemical Journal. 412 (1): 57–63. doi:10.1042/bj20071648. ISSN 0264-6021. PMID 18271758.
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