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

doi:10.1093/NAR/GKZ689

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

Research output: Contribution to journal › Article › peer-review

29 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 language	English
Pages (from-to)	9685-9695
Number of pages	11
Journal	Nucleic Acids Research
Volume	47
Issue number	18
DOIs	https://doi.org/10.1093/NAR/GKZ689
State	Published - 10 Oct 2019

Bibliographical note

Publisher Copyright:
© The Author(s) 2019

Funding

Israel Science Foundation [176/11 to B.K.]; The Chief Scientist Office of the Israel Ministry of Health [3-00000-6014 to B.K.]; The Israel Science Foundation and the National Natural Science Foundation of China (NSFC-ISF) Joint Research Program [2535/16 to B.K.]; Israeli Centers for Research Excellence (I-CORE), Gene Regulation in Complex Human Disease [41/11 to B.K.]; NIH [RO1GM101192 to Y.H.W.]. Funding for open access charge: ISF. Conflict of interest statement. None declared.

Funders	Funder number
Gene Regulation in Complex Human Disease	41/11
NSFC-ISF	2535/16
National Institutes of Health
National Institute of General Medical Sciences	R01GM101192
National Natural Science Foundation of China
Israel Science Foundation	176/11
Israeli Centers for Research Excellence
Office of the Chief Scientist, Ministry of Health	3-00000-6014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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.",

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AU - Sinai, Michal Irony Tur

AU - Salamon, Anita

AU - Stanleigh, Noemie

AU - Goldberg, Tchelet

AU - Weiss, Aryeh

AU - Wang, Yuh Hwa

AU - Kerem, Batsheva

PY - 2019/10/10

Y1 - 2019/10/10

N2 - 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.

AB - 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.

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AT-dinucleotide rich sequences drive fragile site formation

Abstract

Bibliographical note

Funding

UN SDGs

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