DNA Repeats and Genome Instability Mechanisms

DNA repeats—ranging from tandem microsatellites to interspersed transposon-derived elements and inverted palindromes—constitute a significant fraction of eukaryotic genomes. Their propensity to adopt non-B-form conformations, such as hairpins and cruciform structures, creates obstacles to replication fork progression and exposes single-stranded regions susceptible to nuclease attack. Unresolved secondary structures provoke double-strand breaks that are channelled into repair pathways, including non-homologous end joining and homology-directed repair, often mispairing repetitive elements and driving non-allelic homologous recombination. Repeated cycles of chromosome breakage, fusion and bridge formation can yield complex rearrangements, copy-number alterations and aneuploidy. Such instability underlies oncogenic amplification, congenital syndromes and neurodegenerative disorders. Advances in long-read and single-molecule sequencing have illuminated the distribution, dynamics and sequence variation of repeats across populations, emphasising their dual role as agents of genome evolution and as fragile sites. Emerging applications aim to target repeat-derived secondary structures for diagnostic biomarkers and therapeutic intervention in diseases marked by structural variation.

Research from Nature Portfolio

Recent studies have uncovered mechanisms by which palindromic sequences drive locus-specific oncogene amplification. Analyses of breast tumour samples reveal that ERBB2 amplification peaks coincide with enriched inverted duplications, suggesting that fold-back of palindromic repeats initiates breakage–fusion–bridge cycles at this locus. The underlying genomic architecture—characterised by segmental duplications and repeat clusters—appears to predispose the region to recurrent palindromic gene amplification events. These findings highlight structural features that may be exploited to predict amplification hotspots and to develop strategies that stabilise secondary structures in cancer genomes.

DNA Repeats and Genome Instability Mechanisms publication trend

The graph below shows the total number of articles in dna repeats and genome instability mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Direct repeat: Sequences repeated in the same orientation that can misalign to cause deletions or duplications.

Inverted repeat: Two sequence motifs in opposite orientation, capable of annealing to form hairpins or cruciforms.

Palindrome: A symmetric inverted repeat whose halves are reverse complements, often forming stable non-B structures.

Hairpin: A single-stranded DNA secondary structure formed when an inverted repeat folds back on itself.

Cruciform: A four-way junction arising when inverted repeats extrude from double-stranded DNA under supercoiling stress.

Gross chromosomal rearrangement: Large-scale alterations in chromosome architecture, including translocations, inversions, deletions and duplications.

Non-allelic homologous recombination (NAHR): Recombination between repetitive elements at non-allelic loci, leading to structural variation.

Breakage–fusion–bridge cycle: A mechanism of instability in which chromosome ends lacking telomeres fuse and break during mitosis, driving repeated rearrangements.

References

1. Widely spaced and divergent inverted repeats become a potent source of chromosomal rearrangements in long single-stranded DNA regions. Nucleic Acids Research (2023).
2. Palindromic amplification of the ERBB2 oncogene in primary HER2-positive breast tumors. Scientific Reports (2017).
3. A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications. Breast Cancer Research (2012).
4. A reference catalog of DNA palindromes in the human genome and their variations in 1000 Genomes. Human Genome Variation (2020).
5. Structural parameters of palindromic repeats determine the specificity of nuclease attack of secondary structures. Nucleic Acids Research (2021).