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. 2023 Jan;45(1):e2200168.
doi: 10.1002/bies.202200168. Epub 2022 Nov 17.

Chromosomal breaks at the origin of small tandem DNA duplications

Joost Schimmel  1 , Marloes D van Wezel  1 , Robin van Schendel  1 , Marcel Tijsterman  1
Affiliations

Chromosomal breaks at the origin of small tandem DNA duplications

Joost Schimmel et al. Bioessays. 2023 Jan.

Abstract

Small tandem DNA duplications in the range of 15 to 300 base-pairs play an important role in the aetiology of human disease and contribute to genome diversity. Here, we discuss different proposed mechanisms for their occurrence and argue that this type of structural variation mainly results from mutagenic repair of chromosomal breaks. This hypothesis is supported by both bioinformatical analysis of insertions occurring in the genome of different species and disease alleles, as well as by CRISPR/Cas9-based experimental data from different model systems. Recent work points to fill-in synthesis at double-stranded DNA breaks with complementary sequences, regulated by end-joining mechanisms, to account for small tandem duplications. We will review the prevalence of small tandem duplications in the population, and we will speculate on the potential sources of DNA damage that could give rise to this mutational signature. With the development of novel algorithms to analyse sequencing data, small tandem duplications are now more frequently detected in the human genome and identified as oncogenic gain-of-function mutations. Understanding their origin could lead to optimized treatment regimens to prevent therapy-induced activation of oncogenes and might expose novel vulnerabilities in cancer.

Keywords: DNA polymerases; FLT3-ITD; clustered single-strand breaks; double-strand breaks; non-homologous end-joining; small tandem duplications.

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References

REFERENCES

    1. Koh, G., Degasperi, A., Zou, X., Momen, S., & Nik-Zainal, S. (2021). Mutational signatures: emerging concepts, caveats and clinical applications. Nature Reviews Cancer, 21(10), 619-637. https://doi.org/10.1038/s41568-021-00377-7
    1. Hanahan, D. (2022). Hallmarks of cancer: New dimensions. Cancer discovery, 12(1), 31-46. https://doi.org/10.1158/2159-8290.CD-21-1059
    1. Alexandrov, L. B., Kim, J., Haradhvala, N. J., Huang, M. N., Ng, T., A, W., Wu, Y., Boot, A., Covington, K. R., Gordenin, D. A., Bergstrom, E. N., Islam, S. M. A., Lopez-Bigas, N., Klimczak, L. J., McPherson, J. R., Morganella, S., & Consortium, P. (2020). The repertoire of mutational signatures in human cancer. Nature, 578(7793), 94-101. https://doi.org/10.1038/s41586-020-1943-3
    1. Li, Y., Roberts, N. D., Wala, J. A., Shapira, O., Schumacher, S. E., Kumar, K., Khurana, E., Waszak, S., Korbel, J. O., Haber, J. E., Imielinski, M., PCAWG Structural Variation Working Group, Weischenfeldt, J., Beroukhim, R., & Consortium, P. (2020). Patterns of somatic structural variation in human cancer genomes. Nature, 578(7793), 112-121. https://doi.org/10.1038/s41586-019-1913-9
    1. den Dunnen, J. T., Dalgleish, R., Maglott, D. R., Hart, R. K., Greenblatt, M. S., McGowan-Jordan, J., Roux, A. F., Smith, T., Antonarakis, S. E., & Taschner, P. E. (2016). HGVS recommendations for the description of sequence variants: 2016 update. Human Mutation, 37(6), 564-569. https://doi.org/10.1002/humu.22981

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