Research

Banner image of a metaphase spread pointing out breaks in condensed chromosomes

 

Diagram showing mechanisms for common fragile site breakage. Includes figures for replication fork stalling, scarcity of replication origins, and transcription/replication collision.

 

 

Our research focus is to understand the structure and function of unusual DNA sequences in living cells, and how these sequences cause genome instability and lead to human diseases.  Human chromosomal fragile sites have been correlated with the chromosomal deletions and gene rearrangements found in many cancers.  Our studies are aimed at understanding the genesis of breakpoints that occur at or near fragile sites during oncogenesis.

 

Ongoing projects include:

(I) Genome-wide DNA Secondary Structure Analysis to Investigate DNA Fragility (supported by RO1 GM101192-01A1, July 1, 2013- June 30, 2017)

Chromosomal fragile sites, which are regions of the genome that exhibit chromosomal breakage under conditions of mild replication stress, are predicted to form stable DNA secondary structures. We have developed a protocol can narrow down sites of true fragility withiFlow chart depicting the process of using human genome sequences to predict DNA secondary structures that can then be used to generate a threshold from molecularly-defined fragile sites. This threshold can then be used to refine cytogenetically-defined fragile sites and to identify new fragile regions.s.n the current cytogenetically-defined fragile sites, and uncover potential new fragile sites previously unidentified or too small to be observed cytogenetically. The ultimate goal is to create a list of legitimate sites that are prone to DNA breakage caused by the secondary structure-forming mechanism(s), to evaluate genomic stress caused by endogenous and exogenous insults.

Related Publications: (1), (2), (3), (4), (5), (6)

(II) Roles of fragile sites in cancer-causing gene rearrangements (supported by RO1CA113863,Oct 1, 2015 – Sept 2019)

Using thyroid cancer as a model, we investigate the involvement of DNA fragility in the generation of non-radiation-related chromosomal rearrangements in human cells. We demonstrated that fragile sites participate in the generation of RET/PTC rearrangement in thyroid cells, and this allows exploration of the mechanisms of fragility in these regions to extend our understanding of the molecular mechanisms of chromosomal rearrangements in cancer cells.

Related Publications: (1), (2), (3), (4)

Diagram showing the balance between the impact of environmental agents and therapeutic drugs abd fragile site repair with cell type-specific gene expression in the center. All of this contributing to the fragile site breaks and potential cancer-causing mutations.

Diagram of papillary thyroid carcinoma rearrangements RET/PTC1 and RET/PTC3. (III) Alternative DNA/RNA secondary structure in genetic diseases. 

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Over 30 human diseases, mostly neurological and muscular, are associated with expansion of repetitive DNA sequences. Repetitive DNA sequences have the ability to form a variety of secondary structures during normal cellular processes such as replication and transcription due to the unwinding of duplex DNA. Through collaborations, we investigate the mechanism for repeat expansion and disease pathogenesis.

Related Publications: (1), (2), (3)