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Palindrome-Mediated Translocations in Humans: A New Mechanistic Model for Gross Chromosomal Rearrangements.

Inagaki H, Kato T, Tsutsumi M, Ouchi Y, Ohye T, Kurahashi H - Front Genet (2016)

Bottom Line: Indeed, experiments using a plasmid-based model system showed that the formation of non-B DNA is likely the key to palindrome-mediated genomic rearrangements.Some evidence implies a new mechanism that cruciform DNAs may come close together first in nucleus and illegitimately joined.Analysis of PATRR-mediated translocations in humans will provide further understanding of gross chromosomal rearrangements in many organisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health UniversityToyoake, Japan; Genome and Transcriptome Analysis Center, Fujita Health UniversityToyoake, Japan.

ABSTRACT
Palindromic DNA sequences, which can form secondary structures, are widely distributed in the human genome. Although the nature of the secondary structure-single-stranded "hairpin" or double-stranded "cruciform"-has been extensively investigated in vitro, the existence of such unusual non-B DNA in vivo remains controversial. Here, we review palindrome-mediated gross chromosomal rearrangements possibly induced by non-B DNA in humans. Recent advances in next-generation sequencing have not yet overcome the difficulty of palindromic sequence analysis. However, a dozen palindromic AT-rich repeat (PATRR) sequences have been identified at the breakpoints of recurrent or non-recurrent chromosomal translocations in humans. The breakages always occur at the center of the palindrome. Analyses of polymorphisms within the palindromes indicate that the symmetry and length of the palindrome affect the frequency of the de novo occurrence of these palindrome-mediated translocations, suggesting the involvement of non-B DNA. Indeed, experiments using a plasmid-based model system showed that the formation of non-B DNA is likely the key to palindrome-mediated genomic rearrangements. Some evidence implies a new mechanism that cruciform DNAs may come close together first in nucleus and illegitimately joined. Analysis of PATRR-mediated translocations in humans will provide further understanding of gross chromosomal rearrangements in many organisms.

No MeSH data available.


Proposed model for coordinated joining of derivative chromosomes. Two derivative chromosomes have an increased likelihood of having identical junction sequences, indicating that exactly equal-sized deletions occurred in each palindrome center, which then joined to form two junction fragments. This phenomenon cannot be explained by the classical model, where the two double-stranded breakages are processed independently (A). This could happen when the breakpoints of the derivative chromosomes are generated in a coordinated manner (B). (Inagaki et al., 2013; Mishra et al., 2014).
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Figure 2: Proposed model for coordinated joining of derivative chromosomes. Two derivative chromosomes have an increased likelihood of having identical junction sequences, indicating that exactly equal-sized deletions occurred in each palindrome center, which then joined to form two junction fragments. This phenomenon cannot be explained by the classical model, where the two double-stranded breakages are processed independently (A). This could happen when the breakpoints of the derivative chromosomes are generated in a coordinated manner (B). (Inagaki et al., 2013; Mishra et al., 2014).

Mentions: Again, the identical sequences of the two derivative chromosomes imply that the two DNA breakage sites are unlikely to have been processed independently. The two derivative chromosomes were likely to be generated in a coordinated manner. Taken together, in the case of a PATRR-mediate translocation, PATRR appears to extrude cruciform structures at some stage during spermatogenesis. The two cruciform DNA molecules seek each other out and finally join together (Figure 2). In our translocation model system in cultured cells described above, the data suggested that two cleavage processes—cleaved diagonal cleavage of the cruciform structure and cleavage of the tip of the hairpin structure—are involved in translocation development (Inagaki et al., 2013). Our data also suggest that the pathway involves the participation of Artemis and ligase IV, which are components of the V(D)J recombination system that act by bringing two chromosomal sites close together and connecting them. In V(D)J recombination, RAG1 and RAG2 proteins bind the two cleavage sites to hold the resulting ends, both of which are specific for the V(D)J recombination machinery in lymphocytes. Similar mechanism is known in a DNA repair system of non-homologous end joining, in which Ku70/80 holds the two broken end until the subsequent repair machinery associate to process and join the ends (Deriano and Roth, 2013). Artemis and ligase IV as well as DNA-PK and other factors also participate in the joining reactions. It is possible that a part of such systems, or other novel factors might be involved in the contact between the two extruded cruciform structures and in keeping them in position during processing until the two derivative chromosomes are generated. We are now investigating how two cruciform DNA molecules come close together to elucidate the third mechanistic model that leads to recurrent chromosomal translocations in humans. Such investigation of dynamics of the cruciforms in nuclei will shed light on the role of non-B DNAs in gross chromosomal rearrangements in other eukaryotes.


Palindrome-Mediated Translocations in Humans: A New Mechanistic Model for Gross Chromosomal Rearrangements.

Inagaki H, Kato T, Tsutsumi M, Ouchi Y, Ohye T, Kurahashi H - Front Genet (2016)

Proposed model for coordinated joining of derivative chromosomes. Two derivative chromosomes have an increased likelihood of having identical junction sequences, indicating that exactly equal-sized deletions occurred in each palindrome center, which then joined to form two junction fragments. This phenomenon cannot be explained by the classical model, where the two double-stranded breakages are processed independently (A). This could happen when the breakpoints of the derivative chromosomes are generated in a coordinated manner (B). (Inagaki et al., 2013; Mishra et al., 2014).
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Related In: Results  -  Collection

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Figure 2: Proposed model for coordinated joining of derivative chromosomes. Two derivative chromosomes have an increased likelihood of having identical junction sequences, indicating that exactly equal-sized deletions occurred in each palindrome center, which then joined to form two junction fragments. This phenomenon cannot be explained by the classical model, where the two double-stranded breakages are processed independently (A). This could happen when the breakpoints of the derivative chromosomes are generated in a coordinated manner (B). (Inagaki et al., 2013; Mishra et al., 2014).
Mentions: Again, the identical sequences of the two derivative chromosomes imply that the two DNA breakage sites are unlikely to have been processed independently. The two derivative chromosomes were likely to be generated in a coordinated manner. Taken together, in the case of a PATRR-mediate translocation, PATRR appears to extrude cruciform structures at some stage during spermatogenesis. The two cruciform DNA molecules seek each other out and finally join together (Figure 2). In our translocation model system in cultured cells described above, the data suggested that two cleavage processes—cleaved diagonal cleavage of the cruciform structure and cleavage of the tip of the hairpin structure—are involved in translocation development (Inagaki et al., 2013). Our data also suggest that the pathway involves the participation of Artemis and ligase IV, which are components of the V(D)J recombination system that act by bringing two chromosomal sites close together and connecting them. In V(D)J recombination, RAG1 and RAG2 proteins bind the two cleavage sites to hold the resulting ends, both of which are specific for the V(D)J recombination machinery in lymphocytes. Similar mechanism is known in a DNA repair system of non-homologous end joining, in which Ku70/80 holds the two broken end until the subsequent repair machinery associate to process and join the ends (Deriano and Roth, 2013). Artemis and ligase IV as well as DNA-PK and other factors also participate in the joining reactions. It is possible that a part of such systems, or other novel factors might be involved in the contact between the two extruded cruciform structures and in keeping them in position during processing until the two derivative chromosomes are generated. We are now investigating how two cruciform DNA molecules come close together to elucidate the third mechanistic model that leads to recurrent chromosomal translocations in humans. Such investigation of dynamics of the cruciforms in nuclei will shed light on the role of non-B DNAs in gross chromosomal rearrangements in other eukaryotes.

Bottom Line: Indeed, experiments using a plasmid-based model system showed that the formation of non-B DNA is likely the key to palindrome-mediated genomic rearrangements.Some evidence implies a new mechanism that cruciform DNAs may come close together first in nucleus and illegitimately joined.Analysis of PATRR-mediated translocations in humans will provide further understanding of gross chromosomal rearrangements in many organisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health UniversityToyoake, Japan; Genome and Transcriptome Analysis Center, Fujita Health UniversityToyoake, Japan.

ABSTRACT
Palindromic DNA sequences, which can form secondary structures, are widely distributed in the human genome. Although the nature of the secondary structure-single-stranded "hairpin" or double-stranded "cruciform"-has been extensively investigated in vitro, the existence of such unusual non-B DNA in vivo remains controversial. Here, we review palindrome-mediated gross chromosomal rearrangements possibly induced by non-B DNA in humans. Recent advances in next-generation sequencing have not yet overcome the difficulty of palindromic sequence analysis. However, a dozen palindromic AT-rich repeat (PATRR) sequences have been identified at the breakpoints of recurrent or non-recurrent chromosomal translocations in humans. The breakages always occur at the center of the palindrome. Analyses of polymorphisms within the palindromes indicate that the symmetry and length of the palindrome affect the frequency of the de novo occurrence of these palindrome-mediated translocations, suggesting the involvement of non-B DNA. Indeed, experiments using a plasmid-based model system showed that the formation of non-B DNA is likely the key to palindrome-mediated genomic rearrangements. Some evidence implies a new mechanism that cruciform DNAs may come close together first in nucleus and illegitimately joined. Analysis of PATRR-mediated translocations in humans will provide further understanding of gross chromosomal rearrangements in many organisms.

No MeSH data available.