3D genome organization contributes to genome instability at fragile sites

Dan Sarni, Takayo Sasaki, Michal Irony Tur-Sinai, Karin Miron, Juan Carlos Rivera-Mulia, Brian Magnuson, Mats Ljungman, David M Gilbert, Batsheva Kerem

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Abstract

Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features were suggested to underlie CFS instability, however, these features are prevalent across the genome. Therefore, the molecular mechanisms underlying CFS instability remain unclear. Here, we explore the transcriptional profile and DNA replication timing (RT) under mild replication stress in the context of the 3D genome organization. The results reveal a fragility signature, comprised of a TAD boundary overlapping a highly transcribed large gene with APH-induced RT-delay. This signature enables precise mapping of core fragility regions in known CFSs and identification of novel fragile sites. CFS stability may be compromised by incomplete DNA replication and repair in TAD boundaries core fragility regions leading to genomic instability. The identified fragility signature will allow for a more comprehensive mapping of CFSs and pave the way for investigating mechanisms promoting genomic instability in cancer.

Original languageEnglish (US)
Pages (from-to)3613
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Jul 17 2020

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  • Journal Article

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    Sarni, D., Sasaki, T., Irony Tur-Sinai, M., Miron, K., Rivera-Mulia, J. C., Magnuson, B., Ljungman, M., Gilbert, D. M., & Kerem, B. (2020). 3D genome organization contributes to genome instability at fragile sites. Nature communications, 11(1), 3613. https://doi.org/10.1038/s41467-020-17448-2