Cruciform DNA
Folded cruciform structures are characterized by the formation of acute angles between adjacent arms and main strand DNA.
[3] 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.
They also serve a function in epigenetic regulation along with biological implications such as DNA supercoiling, double strand breaks, and targets for cruciform-binding proteins.
[10] Alfred Gierer was one of the first scientists to propose an interaction between proteins and the grooves of specific double-stranded DNA nucleotide sequences.
[11] As tRNA folds on itself in the presence of paired complementary bases, it causes the formation of branches and loops that are both key components in interactions with protein.
Starting in the early 1980s, recognition sites of DNA that formed hairpin structures for a range of cellular proteins were characterized.
Cruciform formation is dependent on several factors including temperature, sodium, magnesium, and the presence of negatively supercoiled DNA.
The negatively supercoiled DNA helix becomes flexible when a cruciform structure forms and intrastrand base pairing occurs.
[10][20] The inverted repeat sequences that suggest cruciform structures, have been found to act as target sites where endonucleases can cleave.
[21][22] An endonuclease from organism Saccharomyces cerevisiae, Mus81-Mms4, has been found to interact with a protein labeled Crp1 that recognizes assumed cruciform structures.
[22] Crp1 was separately identified as a cruciform-binding protein in S. cerevisiae because it had a high affinity to target synthetic inverted repeat sequences.
In bacterial plasmids, RuvA and RuvB repair DNA damage, and are involved in the recombination process of Holliday junctions.
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.
[26] These mutations include single base substitutions and insertions, but more often cruciform structures lead to deletion of genetic material.
Cruciform structures contribute to the instability, translocations, and deletions common in fragile sites by promoting double-stranded breaks.
[27][28] Replication and transcription stalling most often leads to deletions of the cruciform DNA sequence by repair enzymes, similar to the mechanism seen in chromosomal fragile sites.
[28] The high genomic instability of cruciform forming DNA sequences make them prone to mutations and deletions, some of which contribute to the development of cancer.
[7] There are several cellular mechanisms in place to prevent genomic discrepancies caused by cruciform structures, but disruption of these processes can lead to malignancies.
Architectural human oncoproteins, such as DEK, preferentially bind to cruciform structures during replication and transcription to prevent double-stranded breaks or erroneous DNA repair.
[29] Malfunction in architectural oncoproteins, as observed in lung, breast, and other cancers as well as autoimmune disorders, leads to uncontrolled formation of cruciform DNA structures and promotion of double-stranded breaks.
