A new study from Weill Cornell Medicine has uncovered key details about how cells manage telomeres during replication. Using the yeast Candida glabrata as a model, researchers identified how interactions between the CST complex and DNA polymerase α/primase (PP) complex regulate telomerase and help maintain telomere integrity. The findings were published April 17 in Nucleic Acids Research.
Telomeres shorten with each round of cell division, and telomerase temporarily extends them by producing a DNA overhang. A fill-in synthesis process then completes the shorter strand. When this step fails, it can mimic DNA damage and trigger harmful repair responses.
The researchers found that DNA polymerase α is recruited to chromosome ends via the CST complex. “This both regulates telomerase activity and protects chromosome ends from damaging repairs,” said Neal Lue, senior author and professor at Weill Cornell Medicine.
Building on work that showed CST stimulates polymerase α in vitro, the team collaborated with the Spanish National Cancer Research Centre to compare yeast and human protein structures. They introduced mutations that disrupted CST-PP binding and tracked the effects. In one group of mutants, telomeres extended in both strands without signs of DNA damage. “Our data suggest that bringing in the CST-PP complex is a critical step in terminating telomerase activity,” Lue said.
In another group, cells grew slowly and displayed telomeres of uneven lengths with increased single-stranded DNA. “We don’t think the loss of fill-in synthesis activity is the only reason for the telomere abnormalities,” Lue explained. “We think that when you disrupt the CST-PP complex, as with these mutants, the telomeres become accessible to DNA repair factors, which causes many different problems with the telomeres.”
“Our study provided the first in vivo evidence that PP is not only making DNA at telomeres, but also protecting them,” added Eun Young Yu, assistant professor at Weill Cornell Medicine.
The results may help explain disorders such as Coats plus syndrome, where patients have mutations in CST and prematurely shortened telomeres. They may also inform new approaches to cancer therapy. Since cancer cells often hijack telomerase to support uncontrolled growth, targeting CST protein interactions could be a potential strategy to limit tumor cell proliferation.
Publication Details
Kimberly Calugaru, Eun Young Yu, Sophie Huang, Nayim González-Rodríguez, Javier Coloma, Neal F Lue, The yeast CST and Polα/primase complexes act in concert to ensure proper telomere maintenance and protection, Nucleic Acids Research, Volume 53, Issue 7, 24 April 2025, gkaf245, https://doi.org/10.1093/nar/gkaf245
Telomeres shorten with each round of cell division, and telomerase temporarily extends them by producing a DNA overhang. A fill-in synthesis process then completes the shorter strand. When this step fails, it can mimic DNA damage and trigger harmful repair responses.
The researchers found that DNA polymerase α is recruited to chromosome ends via the CST complex. “This both regulates telomerase activity and protects chromosome ends from damaging repairs,” said Neal Lue, senior author and professor at Weill Cornell Medicine.
Building on work that showed CST stimulates polymerase α in vitro, the team collaborated with the Spanish National Cancer Research Centre to compare yeast and human protein structures. They introduced mutations that disrupted CST-PP binding and tracked the effects. In one group of mutants, telomeres extended in both strands without signs of DNA damage. “Our data suggest that bringing in the CST-PP complex is a critical step in terminating telomerase activity,” Lue said.
In another group, cells grew slowly and displayed telomeres of uneven lengths with increased single-stranded DNA. “We don’t think the loss of fill-in synthesis activity is the only reason for the telomere abnormalities,” Lue explained. “We think that when you disrupt the CST-PP complex, as with these mutants, the telomeres become accessible to DNA repair factors, which causes many different problems with the telomeres.”
“Our study provided the first in vivo evidence that PP is not only making DNA at telomeres, but also protecting them,” added Eun Young Yu, assistant professor at Weill Cornell Medicine.
The results may help explain disorders such as Coats plus syndrome, where patients have mutations in CST and prematurely shortened telomeres. They may also inform new approaches to cancer therapy. Since cancer cells often hijack telomerase to support uncontrolled growth, targeting CST protein interactions could be a potential strategy to limit tumor cell proliferation.
Publication Details
Kimberly Calugaru, Eun Young Yu, Sophie Huang, Nayim González-Rodríguez, Javier Coloma, Neal F Lue, The yeast CST and Polα/primase complexes act in concert to ensure proper telomere maintenance and protection, Nucleic Acids Research, Volume 53, Issue 7, 24 April 2025, gkaf245, https://doi.org/10.1093/nar/gkaf245