AT-dinucleotide rich sequences drive fragile site formation

Michal Irony Tur Sinai, Anita Salamon, Noemie Stanleigh, Tchelet Goldberg, Aryeh Weiss, Yuh Hwa Wang, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Common fragile sites (CFSs) are genomic regions prone to breakage under replication stress conditions recurrently rearranged in cancer. Many CFSs are enriched with AT-dinucleotide rich sequences (AT-DRSs) which have the potential to form stable secondary structures upon unwinding the double helix during DNA replication. These stable structures can potentially perturb DNA replication progression, leading to genomic instability. Using site-specific targeting system, we show that targeted integration of a 3.4 kb AT-DRS derived from the human CFS FRA16C into a chromosomally stable region within the human genome is able to drive fragile site formation under conditions of replication stress. Analysis of >1300 X chromosomes integrated with the 3.4 kb AT-DRS revealed recurrent gaps and breaks at the integration site. DNA sequences derived from the integrated AT-DRS showed in vitro a significantly increased tendency to fold into branched secondary structures, supporting the predicted mechanism of instability. Our findings clearly indicate that intrinsic DNA features, such as complexed repeated sequence motifs, predispose the human genome to chromosomal instability.

Original languageAmerican English
Pages (from-to)9685-9695
Number of pages11
JournalNucleic Acids Research
Volume47
Issue number18
DOIs
StatePublished - 10 Oct 2019

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© The Author(s) 2019

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