Researchers at the University of Pittsburgh have uncovered an unexpected relationship between two of the genome’s most distinct chromosomal structures, revealing how aggressive cancers that rely on the alternative lengthening of telomeres (ALT) pathway may adapt to sustain their growth.
The study, published in Nature, shows that centromeric DNA sequences and chromatin components become incorporated into telomeres in ALT-positive cancers, creating a previously unrecognized genomic signature that appears to help maintain telomere integrity. The findings provide new insight into how cancers driven by ALT evolve and may ultimately reveal vulnerabilities that could be therapeutically exploited.
“Telomeres and centromeres are not known to interact,” said senior author Roderick O’Sullivan, PhD, professor of pharmacology and chemical biology at the University of Pittsburgh and UPMC Hillman Cancer Center. “They’re not known to occupy the same regions of the genome. This is a really bizarre and unique event that is being captured in this specifically pathogenic context.”
ALT, or alternative lengthening of telomeres, is a specialized telomere maintenance mechanism used by approximately 5% to 10% of cancers. Unlike most tumors, which reactivate telomerase to extend telomeres and achieve replicative immortality, ALT-positive tumors rely on recombination-based mechanisms to lengthen chromosome ends. ALT is particularly enriched in aggressive subsets of sarcomas, gliomas, pancreatic neuroendocrine tumors, and other mesenchymal-derived cancers.
Although ALT has long been associated with genome instability and epigenetic dysregulation, researchers had not previously identified specific genomic rearrangements generated during ALT activation.
In the new study, O’Sullivan and colleagues discovered that centromeric DNA repeats become inserted into telomeric regions specifically in ALT cancer cell lines and primary pediatric neuroblastoma samples. The findings challenge a long-standing assumption that telomeres and centromeres remain physically and functionally separated within the nucleus.
“Centromeres and telomeres typically occupy exclusive nuclear territories,” said co-corresponding author Yael Nechemia-Arbely, PhD. “When we first saw the results, I was very skeptical. It took a long time and a lot of quantification and looking at it from many different angles to convince us that this was real.”
The investigators traced the phenomenon to loss of ATRX, a chromatin-remodeling protein frequently mutated in ALT-positive cancers and widely used as a biomarker of ALT status. Loss of ATRX has long been linked to telomere dysfunction, but the new work suggests it may simultaneously destabilize centromeric regions, creating conditions that enable interactions between two chromosomal domains that are normally kept apart.
“What we think is going on is that when ATRX is gone, you’ve not only destabilized telomeres, but you’ve also destabilized centromeres,” O’Sullivan said. “Now you have these two exposed domains that either through chance or necessity are interacting, and the ultimate byproduct of that transaction is the insertion of DNA repeats from the centromere into the telomere.”
The researchers found that epigenetic dysregulation caused by ATRX loss, together with DNA hypomethylation, promoted acquisition of these centromeric chromatin signatures at telomeres.
Ragini Bhargava, PhD, co-corresponding author of the study, said the findings expand current understanding of how ALT-associated telomeres evolve. “For a long time, the field viewed ALT as telomeres recombining with other telomeres,” Bhargava said. “What this study is showing is that when you lose ATRX, telomeres become prone not only to recombination within telomeres but also with other parts of the genome. One of those regions is the centromere, which should be highly protected and spatially very far away from telomeres.”
The team also demonstrated that the centromeric material incorporated into telomeres is not merely a passive byproduct of genome instability. Functional experiments showed that disrupting HJURP-mediated deposition of CENP-A compromised telomere integrity, impaired ALT activity, and triggered aberrant telomeric mitotic DNA synthesis. Those results suggest that centromeric chromatin becomes functionally integrated into the telomere maintenance machinery of ALT cancers.
“What’s interesting is that the DNA repeats from the centromere are actually doing something,” O’Sullivan said. “They’re bringing machinery to the telomere, and somehow the telomere is adapting and using that to protect itself so that the cancer cell can keep growing.”
The work points to a previously unrecognized form of interchromosomal communication that may help explain how ALT-positive tumors survive despite extensive genomic instability.
Clinically, the findings are not yet ready to translate into a therapeutic strategy, the authors cautioned. However, they may eventually provide new biomarkers or reveal dependencies unique to ALT-driven tumors.
“We have a documentation of something within the series of events that happens as these cells become highly detrimental,” O’Sullivan said. “This is a new signature of that process.”
Because proteins involved in centromere function are essential for normal cellular processes, directly targeting the newly identified pathway may prove challenging. Nevertheless, the researchers believe the discovery opens a new area of investigation into ALT biology.
“In my view, this is the beginning,” O’Sullivan said. “There could be other machinery that these centromere proteins are bringing that will provide a vulnerability that could be targeted.”
The findings suggest that aggressive ALT-positive cancers have evolved an unexpected strategy for preserving chromosome ends, co-opting centromeric DNA and chromatin to reinforce telomere function. In doing so, they reveal a previously hidden connection between two of the genome’s most fundamental structures and provide new insight into how cancer cells sustain limitless growth.
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