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Alternative Lengthening of Telomeres in Cancer

Wednesday, December 7, 2022

10:00 AM-12:00 PM

BIOMED PhD Research Proposal

Alternative Lengthening of Telomeres in Cancer

Kaitlin Raseley, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Ming Xiao, PhD
School of Biomedical Engineering, Science and Health Systems
Drexel University

In humans, telomeres are nucleoprotein complexes made up of tandem 5′TTAGGG3′ DNA repeats and associated proteins located at the ends of all 46 chromosomes. Telomere (TTAGGG)n tract loss beyond a certain threshold changes the telomere structure (“uncapping”), which causes telomere dysfunction and leads to senescence or apoptosis.  

The cancer cells utilize one of the two Telomere Maintenance Mechanisms (TMM) to maintain their telomeres during uncontrolled proliferation,  telomerase, and alternative lengthening of telomeres (ALT).  ALT is commonly thought to occur in about 10–20% of all tumors and relies on many DNA damage response (DDR) proteins, including those involved in the homology-dependent repair (HDR) pathway.

Here we use a Single Molecule Telomere Assay Optical Mapping (SMTA-OM) assay, capable of quantifying individual telomeres from single molecules across all chromosomes to analyze the telomeric features in ALT+ cancer cells. ALT+ cells display some unique features including increased fusions/internal telomere-like sequence (ITS+), fusions/internal telomere-like sequence loss (ITS-), telomere-free ends (TFE), superlong telomeres, and telomere length heterogeneity, compared to Telomerase+ (TEL+) cancer cells. The readouts may be used as biomarkers for ALT+ cancer cells. The differences seen in the SMTA-OM assay results between ALT+ cancer cells could also be used to subtype the ALT+ cancers and monitor cancer therapy.

We applied the SMTA-OM for understanding the mechanism of ALT pathways. Our results show targeting telomeric sequence with a catalytically inactive Cas9 (dCas9) physically prevents DNA replication machinery progression. Blocking replication machinery led to an increase in DNA damage and an increase in unique structural changes in the telomere and adjacent subtelomere, likely resulting from the upregulation of the ALT pathways.  

We also plan to combine the high-resolution SMTA-OM with a newly developed sequencing protocol, potentially identifying the chromosomal origins of the newly fused portion in the fusion DNA molecules. It is currently unknown whether the molecular fusions are occurring between the same chromosome arm(s) or whether interactions between chromosomes are completely random during the breakage-fusion-bridge (BFB) cycle after activation of the ALT pathway. It is essential to continue investigating the behavior of the ALT pathway in ALT+ cancer cells, especially at the single-molecule level, and these proposed methods make it possible. Despite recent advances in this area of research, there are still critical unanswered questions.

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