Why are palindromes important

These genes provide the blueprint for the Cas proteins - namely, the enzymes that cut the DNA strand. Palindromes in the genome. Open in new window. Current Opinion in Genetics and Development. Marshall Graves JA. Weird animal genomes and the evolution of vertebrate sex and sex chromosomes.

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Multiple and independent cessation of recombination between avian sex chromosomes. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content. Conservation of Y-linked genes during human evolution revealed by comparative sequencing in chimpanzee.

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The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Two novel mouse genes mapped to chromosome Yp are expressed specifically in spermatids. Mammalian Genome. Fisher RA. The evolution of dominance. Biological Reviews. Gene duplication and the genome distribution of sex-biased genes. International Journal of Evolutionary Biology. Sex-dependent selection differentially shapes genetic variation on and off the guppy Y chromosome.

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The human Y chromosome, in the light of evolution. Nature Reviews Genetics. Hurst LD. Segmental duplications arose during primate evolution and maintain high sequence identity between duplicated regions [ 88 ]. For example, palindromes P1—P8 on the male-specific section of chromosome Y span dozens of genes, many of which are essential for spermatogenesis.

It is considered that these palindromes have an important evolutionary purpose since they allow intrachromsomal recombination in an otherwise non-recombining chromosome. Intrachromosomal gene conversion can protect against deleterious mutations, but also having an extra copy of these genes can enhance the adaptive evolution of chromosome Y [ 89 ]. However, recombination between palindrome arms can result in formation of isodicentric chromosome Y [ 90 ] and recombination between different Y-specific palindromes can result in massive deletion [ 91 , 92 ], all known causes of a range of sex-linked reproductive disorders, including relatively common spermatogenic failure [ 93 ].

Other segmental duplications have also been identified as fragile sites as well. They do not share any significant degree of homology between them, yet, not surprisingly given their palindromic nature, they are often sites of chromosome breakage and genetic rearrangements [ 95 ]. Palindromes PATRR11 approximately bp long and PATRR22 approximately bp long , located on chromosomes 11 and 22, respectively, are involved in the most common recurrent non-Robertsonian translocation in the human genome Figure 4 which is the underlying cause of Emanuel syndrome [ 96 ].

Reciprocal translocation with breakpoints in these palindromic sequences produces balanced carriers which are, for the most part, healthy. They do have an increased risk of developing breast cancer [ 97 ], as well as infertility issues and recurrent pregnancy losses. However, if the small derivative of chromosome 22 produced by translocation is passed on alongside the normal chromosome set, the zygote is viable.

Unfortunately, such children of balanced carriers suffer from Emanuel syndrome which is characterized by a range of psychical disorders involving heart and kidney function as well as mental retardation [ 98 ]. However, offspring who inherit the supernumerary derivative der 22 alongside the normal chromosomal set suffer from Emanuel syndrome.

Approximately 1 in 10, DNA aliquots were positive for the translocation t 11;22 PCR product, indicating de novo translocation in sperm [ ]. However, using the same methodology, the authors found no evidence of de novo t 11;22 translocation in blood and cheek swab cells from the same men, nor in lymphoblastoid cell lines and cultured fibroblasts. This points to the conclusion that de novo t 11;22 translocations occur during gametogenesis. Moreover, although a too small number of female oocytes are available to perform similar testing, there was some indication that occurrence of those de novo t 11;22 translocations might be sperm-specific.

Ohye et al. Due to the polymorphism between PATRR sequences originating from the mother and father, they were able to determine that in all eight cases, the de novo t 11;22 translocation was of paternal origin. The authors proposed that sperm specificity does exist, and it could be explained by a translocation occurring due to the palindrome-mediated instability during DNA replication. Namely, there is a great difference in the number of cell divisions and thus DNA replications in pre-meiotic gametogenic cells in males and females—around divisions until adulthood and an additional 23 each year in spermatogenesis vs.

However, although the frequency of mutations caused by replication errors as well as the frequency of some non-recurrent translocations in sperm does increase with age in men [ , , ], this is not the case for de novo t 11;22 translocation [ ]. In another line of research, the same research group demonstrated that, if there is sufficient negative superhelicity of DNA, PATRRs can extrude into a cruciform when cloned on non-replicative plasmids in human cells [ , ].

Further, the most recent experimental evidence by Correl-Tash et al. They used sister chromatid exchanges SCEs observed in the metaphase chromosome spread using a florescent microscope in samples where PATRR regions were labeled with florescent probes. Since SCEs indicate sites at which DSBs occur and are repaired, they can be used as an indirect measure of genetic instability [ , ].

This is in accordance with the fact that after reciprocal translocation, the recombined PATRR sequences are no longer palindromic and thus no longer pose a threat to genome stability. Moreover, using the same methodology, they showed that PATRRs can result in cruciform formation, leading to an increase in DSB frequency and subsequent repair in spermatogenic cells, but this increase is not higher than in mitotic cells. The explanation for most de novo PATRR-mediated translocation occurrences possibly lies in some specific DSB response or repair mechanism during gametogenesis.

Moreover, using the immunofluorescence labeling method and 2D3 cruciform binding antibody, Feng et al. Interestingly, cruciform foci were detected in different phases of oocyte growth but were no longer present in fully grown oocytes characterized by silencing of transcription activities, chromatin condensation and formation of a Hoechst-positive ring-like structure surrounding the nucleolus. X, indicating that in normal oocytes, a cruciform-induced DSB is probably rare.

Additionally, Feng et al. Since DNA transcription induces a significant amount of negative superhelicity, they proposed that the transcription might be a driving process for cruciform extrusion. PATRR17 is located in the intron of the NF1 gene, and a t 17;22 translocation which led to inactivation of the NF1 gene was found in several patients with neurofibromatosis type 1 [ , ]. Recurrent t 8;22 translocation and inheritance of supernumerary derivative chromosome der 22 t 8;22 are linked to a syndrome characterized by ear and extremity abnormalities, in addition to mild mental retardation [ ].

Non-recurrent translocations involving PATRRs on chromosomes 4, 1, 3 and 9 were also detected [ , , , ]. Additionally, there are examples where investigation of underlying molecular causes of various conditions in humans leads to the discovery of a palindrome in the genome clearly capable of instigating DNA rearrangements. In three unrelated families in Mexico and China, congenital generalized hypertrichosis excessive hair growth all over the body was linked to insertions mediated by a bp palindrome located on chromosome X [ , ].

Throughout this review, we tried to summarize the current state of knowledge on various aspects and consequences of compromised genome stability due to the presence of recombinogenic palindromic sequences. Although occasionally it appears that the research in this filed progresses more slowly than in some other areas due to the difficulties in the cloning and sequencing of DNA palindromes, recent advancements in our understanding of palindrome-instigated genome instability described in this review show that this subject holds the interest of researchers.

Future research in this field will, on the one hand, continue to be focused on molecular mechanisms and protein players involved in palindrome recombinogenicity. It is important to understand when, why and under which conditions a certain palindromic sequence, which was stably replicated and inherited through numerous cell divisions, initiates genetic recombination, possibly with devastating consequences for the cell and organism.

When it comes to cancer cells, genetic rearrangements are often abundant and complex, so it can be difficult to unravel the initiating and subsequent chain of events leading to a certain genotype. Undoubtedly, palindromic gene amplifications are an important mechanism involved in carcinogenesis.

However, palindromes and inverted repeats preexisting in the genome could have a much greater role in initiating recurrent recombination events during carcinogenesis than is currently appreciated. Therefore, it is important to continue the deep sequencing efforts to fill the gaps in the human genome sequence which likely harbor multiple recombinogenic palindromic sequences, but also to analyze as much individual cancer genomes as possible and link them to specific cancer pathophysiology and treatment outcomes.

Hopefully, with enough data analyzed, patterns will emerge which can improve diagnostics as well as the choice of appropriate treatment, but perhaps which can also uncover markers signifying elevated risk even before the disease onset.

National Center for Biotechnology Information , U. Int J Mol Sci. Published online Mar Miroslav Chovanec, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Feb 15; Accepted Mar 8. Abstract A palindrome in DNA consists of two closely spaced or adjacent inverted repeats.

Keywords: DNA palindromes, quasipalindromes, palindromic amplification, palindrome-mediated genetic recombination, carcinogenesis. Introduction As the exploration of various genomes, including our own, moves forward thanks to ever more advanced and more easily available techniques, it is becoming clear that the genome is much more than the assembly of genes. The Recombinogenic Nature of Palindromic Sequences 2. DNA Palidromes Can Form Secondary Structures A palindrome in DNA is a sequence consisting of two identical or highly similar inverted repeats which are either adjacent to one another or separated by a spacer region Figure 1 a.

Open in a separate window. Figure 1. Molecular Mechanisms of Palindrome Recombinogenicity Molecular mechanisms of palindrome recombinogenicity have been investigated in model organisms Escherichia coli and Saccharomyces cerevisiae as well as in human cells. Figure 2. Replication-Independent Palindrome Recombinogenicity The cruciform structure in dsDNA can be cleaved at the base by a structure-specific endonuclease.

Replication-Dependent Palindrome Recombinogenicity During DNA replication, the palindromic sequence can result in the formation of a hairpin in the single-stranded lagging strand which can cause replication stalling and a double-strand break. Palindromic Amplifications in Cancer Genetic instability resulting in various DNA rearrangements is one of the hallmarks of cancer cells. Figure 3. Relatively Short Palindromes in the Genome Can Facilitate the Initiating Event of Palindromic Amplification through the Fold-Back Priming Mechanism Furthermore, the initiation of palindromic gene amplifications in cancer cells can also be explained by the fold-back priming mechanism Figure 3 , right panel.

Longer Palindromes in the Genome Are Fragile Sites Which Can Lead to Palindromic Duplication Moreover, if a palindrome present in the genome is long enough to have the potential to extrude into a cruciform structure, the resolution of the cruciform by an endonuclease also leads to the formation of hairpin-capped chromosome ends and potentially to palindromic chromosome formation Figure 3 , middle panel.

Challenges in Decyphering the Initiating Event Responsible for Palindromic Amplifications in Cancer When it comes to various types of tumors isolated from patients, it can be difficult to pinpoint the initial mechanism which led to gene amplifications since the initial amplification is followed by subsequent rearrangements.

Bioinformatics in Quest for DNA Palindromes The effort to estimate the abundance and distribution of DNA palindromes in genomes greatly relies on the use of bioinformatics tools to analyze genome sequence data. From Short Interspersed Elements SINEs to Segmental Duplications—Possibilities for Palindrome Occurrence in the Human Genome Given the great number of various repeated sequences in the human genome, it is not surprising that they can be found in various relations to one another, such as direct tandem repeats as well as closely spaced inverted repeats, i.

Figure 4. Concluding Remarks Throughout this review, we tried to summarize the current state of knowledge on various aspects and consequences of compromised genome stability due to the presence of recombinogenic palindromic sequences.

Funding This research received no external funding. Conflicts of Interest The authors declare no conflict of interest. References 1. Cruciform structures are a common DNA feature important for regulating biological processes.

BMC Mol. Murchie A. The mechanism of cruciform formation in supercoiled DNA: Initial opening of central basepairs in salt-dependent extrusion. Nucleic Acids Res. Courey A. Cruciform formation in a negatively supercoiled DNA may be kinetically forbidden under physiological conditions. Furlong J. Localized chemical hyperreactivity in supercoiled DNA. Evidence for base unpairing in sequences that induce low-salt cruciform extrusion.

Size-dependent antirecombinogenic effect of short spacers on palindrome recombinogenicity. DNA Repair. Lilley D. The inverted repeat as a recognizable structural feature in supercoiled DNA molecules.

Mizuuchi K. T4 endonuclease VII cleaves holliday structures. Sullivan K. Influence of cation size and charge on the extrusion of a salt-dependent cruciform. Ramreddy T. Real-time detection of cruciform extrusion by single-molecule DNA nanomanipulation.

Vologodskii A. The relaxation time for a cruciform structure in superhelical DNA. FEBS Lett. Benham C. Extrusion of an imperfect palindrome to a cruciform in superhelical DNA: Complete determination of energetics using a statistical mechanical model.

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Dasgupta U. Sinden R. On the deletion of inverted repeated DNA in Escherichia coli: Effects of length, thermal stability, and cruciform formation in vivo. Chalker A. The effects of central asymmetry on the propagation of palin-dromic DNA in bacteriophage lambda are consistent with cruciform extrusion in vivo. Lobachev K. Factors affecting in-verted repeat stimulation of recombination and deletion in Saccharomyces cerevisiae.

InvertedAlurepeats unstable in yeast are excluded from the human genome. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

In mammals, evolution maintained this unique palindromic arrangement, suggesting that it is functionally significant. Lymphopoiesis is coupled with programmed accessibility of Ig genes to transcription and to several major transcription-dependent DNA-remodelling events 1 , 2. The gene-targeting vector replaced the Inserting hs3a in inverted orientation allowed us to completely suppress any dyad symmetry around hs1,2 without deleting any enhancer sequence Fig.

The main diagonal represents the sequence alignment with itself. Parallel lines to the main diagonal represent repetitive patterns within the sequence that is, tandem repeat , whereas perpendicular lines to the main diagonal represent similar but inverted sequences, thus allowing to identify the palindromic structures dotted lines.

Interactions with cognate antigens recruit activated B cells into germinal centres where they undergo SHM in V D J exons for the generation of high-affinity antibodies. Mutation frequencies of 1. SHM frequency was markedly reduced by more than fourfold, at 0. Mean values from six mice for all genotypes were reported 8—12 weeks old, male and female.

Same mice as in a. We next investigated the mechanism underlying the SHM alteration. SHM correlates with transcription In the present study, IgH primary transcription location of the probe is shown in Fig. Together with transcription, modified histones, characteristic of active chromatin, constitute hallmarks of the accessibility to SHM factors.

ChIP experiments probes located are shown in Fig. This shows a synergistic role of enhancers and of the palindromic architecture for induction of epigenetic modifications and chromatin accessibility. As shown in Fig. Background ChIP signals from mock samples with irrelevant antibody were subtracted. ChIP experiments were done in A and B locations as in a. Same immunisation protocol as in b. One representative experiment out of six one mouse per experiment is shown 8- to week-old mice, male and female.

To determine whether results on GLT translated to a decreased CSR, we appreciated by flow cytometry the number of cells switching to a particular isotype after in vitro stimulation. Levels of H3K4me3 Fig. One representative experiment out of five is shown 8- to week-old mice, male and female. One representative experiment out of five is shown left part.

One representative experiment out of three is shown 8- to week-old mice, male and female. Antibody levels, detected by ELISA, are expressed in arbitrary units by comparison with control plasma values. Time after immunisation is indicated in days. One representative experiment out of two is shown. SHM in V H genes was markedly affected by the palindromic deconstruction.

These data do not formally exclude the hypothesis that the reduction in distances between the enhancers alone accounts for our SHM observation. For other enhancers, dependence on proper spatial organisation and spacing has been reported These differences probably relate to the specific structures of germline promoters and of S regions, as the number of G-clusters to initiate R loops, the number of WGCW sites for AID deamination and distance to promoter are of key importance for CSR efficiency However, the induction of these two processes is different.

Although S regions form long R-loops because of to the high level of transcription and their repetitive sequence, V regions display short patches of ssDNA that require the assembly of protein—DNA complex AID is, evolutionarily, the first enzyme known to improve immune diversity by SHM, and it is present as early as the primordial jawed vertebrates; AID-induced CSR begins later, with the first amphibians 32 , 33 , Understanding differences of the pathways that contribute to CSR and SHM will help us understand the mechanisms for antibody regulation and diversity.

The ES cell line E14 was derived from the inbred mouse strain Germline transmission in heterozygous mutant mice was checked by specific PCR. Mutant mice were mated with cre-transgenic mice.