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Role of DNA secondary structures in fragile site breakage along human chromosome 10

Laura W Dillon1, Levi C T Pierce, Maggie C Y Ng

  • 1Department of Biochemistry, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016, USA.

Human Molecular Genetics
|January 9, 2013
PubMed

Insights

Alternative DNA secondary structures can cause DNA breakage, leading to cancer. This study found that common fragile sites have a higher potential for forming these structures, suggesting a link to disease.

Area of Science:

  • Genetics
  • Molecular Biology
  • Genomic Instability

Background:

  • Alternative DNA secondary structures are implicated in DNA breakage and disease.
  • Chromosomal fragile sites are prone to breakage under replication stress and predicted to form DNA secondary structures.
  • Previous studies have not systematically evaluated the secondary structure-forming potential of fragile sites.

Purpose of the Study:

  • To computationally predict and analyze DNA secondary structure formation in human fragile sites.
  • To compare the secondary structure-forming ability between fragile and non-fragile DNA sequences.
  • To identify potential fragile regions and validate computational predictions using experimental assays.

Main Methods:

  • Utilized the Mfold program to predict DNA secondary structure formation on human chromosome 10.
  • Analyzed sequence segments for their potential to form secondary structures.
  • Employed in vitro detection of alternative DNA structures and a DNA breakage cell assay for validation.

Main Results:

  • Aphidicolin (APH)-induced common fragile sites exhibit a higher density of segments with strong secondary structure-forming potential compared to non-fragile DNA.
  • Refined fragile site boundaries and identified potential fragile regions within non-fragile DNA based on secondary structure analysis.
  • Validated computational predictions through in vitro and cellular assays, showing concordance with disease-associated genomic regions.

Conclusions:

  • DNA secondary structures play a significant role in common fragile site instability.
  • Developed a systematic computational method for identifying potential fragile sites based on secondary structure analysis.
  • Provides a mechanistic link between DNA secondary structures and the development of human diseases like cancer.

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