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AT-dinucleotide rich sequences drive fragile site formation
Michal Irony-Tur Sinai1, Anita Salamon2, Noemie Stanleigh1
1Department of Genetics, The Life Sciences Institute, The Hebrew University of Jerusalem, 9190401, Israel.
Nucleic Acids Research
|August 15, 2019
Summary
Common fragile sites (CFSs) are DNA regions prone to breakage. Introducing AT-dinucleotide rich sequences from CFSs can induce fragile sites and genomic instability, even in stable regions.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Common fragile sites (CFSs) are genomic regions susceptible to breakage during DNA replication, particularly under stress.
- Many CFSs contain AT-dinucleotide rich sequences (AT-DRSs) that can form stable secondary structures, potentially hindering replication.
- Such structural impediments are hypothesized to contribute to genomic instability and cancer development.
Purpose of the Study:
- To investigate whether AT-DRSs can induce fragile site formation in a stable genomic location.
- To determine if integrated AT-DRSs exhibit secondary structure formation in vitro.
- To elucidate the role of intrinsic DNA sequence features in driving chromosomal instability.
Main Methods:
- Site-specific integration of a 3.4 kb AT-DRS from the human CFS FRA16C into a stable chromosomal region.
- Induction of replication stress to assess fragile site formation.
- Analysis of >1300 integrated X chromosomes for gaps and breaks.
- In vitro analysis of AT-DRS secondary structure formation.
Main Results:
- Targeted integration of the AT-DRS successfully induced fragile site formation at the integration locus under replication stress.
- Recurrent gaps and breaks were observed at the integration site in over 1300 analyzed X chromosomes.
- In vitro studies confirmed that the AT-DRS sequences possess a high propensity for forming branched secondary structures.
Conclusions:
- Intrinsic DNA sequence features, specifically AT-DRSs, can drive the formation of common fragile sites and chromosomal instability.
- The ability of AT-DRSs to form stable secondary structures is a key mechanism underlying replication stress-induced genomic instability.
- These findings highlight the importance of DNA sequence composition in maintaining genome integrity and its implications in cancer.
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