In a groundbreaking study from Weill Cornell Medicine, scientists have unveiled new molecular insights into how cells meticulously preserve the integrity of chromosome ends during cell division. This intricate process, fundamental to cellular health, involves protein complexes that regulate the activity of telomerase—the enzyme that replenishes protective chromosome end structures called telomeres. Utilizing the model organism yeast, researchers illuminated previously obscure protein interactions that temper telomerase, thereby preventing unchecked cell proliferation or premature cellular aging. Published on April 17 in the esteemed journal Nucleic Acids Research, this work propels the scientific community closer to deciphering the enigmatic mechanisms underpinning aging and cancer.
Chromosomes, the carriers of genetic information, are capped by telomeres which act as guardians of genomic stability. During cell division, chromosomes are duplicated, but the replication machinery encounters challenges at these telomeric ends. Specifically, while duplicating DNA, standard DNA polymerases struggle to fully replicate the extremities of linear chromosomes, resulting in gradual telomere shortening with each division—a hallmark of cellular aging. Telomerase intervenes by extending one strand of the telomere, generating a single-stranded overhang. This overhang must then be accurately filled in by the fill-in synthesis machinery to maintain telomere length and structural integrity. Failure in this process flags the chromosome ends as DNA damage, potentially triggering deleterious repair pathways and eventual cell death.
Central to this regulation are two protein assemblies: the CST complex, composed of three subunits, and the DNA polymerase α/primase (PP) complex. These groups coordinate to execute the fill-in synthesis necessary for telomere maintenance. The study, led by Dr. Neal Lue and colleagues, discovered that DNA polymerase α is actively recruited to chromosome termini where it forms a functional assembly with the CST complex. This partnership not only moderates telomerase elongation activity but also protects chromosome caps from erroneous DNA repair mechanisms, thereby safeguarding genomic fidelity.
The investigation capitalized on the powerful genetics and biochemistry of yeast, which share conserved telomere maintenance pathways with humans, enabling precise dissection of fundamental molecular processes. Previous research by the team purified CST and PP proteins from Candida glabrata, revealing CST’s stimulation of polymerase α activity in vitro. Yet, the precise physical interactions remained elusive until recently. Collaborating with structural biologists at the Spanish National Cancer Research Centre, the researchers applied computational modeling to demonstrate that yeast CST and PP complexes adopt conformations analogous to those observed in human proteins, offering a vital comparative framework.
With this structural blueprint, the team engineered specific mutations designed to disrupt CST-PP interactions, enabling in vivo assessment of the functional consequences. Their observations revealed two distinct phenotypes. In some mutants, telomeres elongated in the absence of DNA damage signals, suggesting partial defects in terminating telomerase action, although complementary fill-in synthesis persisted. These mutants reflect a nuanced imbalance wherein telomerase activity is inadequately restrained but overall telomere synthesis continues, underscoring the complex regulatory mechanics of telomere elongation termination.
Conversely, another class of mutants exhibited stunted growth accompanied by heterogeneous telomere length abnormalities including both elongation and shortening, alongside accumulations of single-stranded DNA overhangs. These significant disturbances in telomere architecture do not seemingly arise from fill-in synthesis failure alone. Instead, loss of CST-PP complex integrity appears to render telomeres vulnerable to invasive DNA repair factors, which introduce pathological alterations. This phenomenon highlights CST-PP’s vital role not just in DNA synthesis but in shielding chromosome ends from harmful processing events. First author Dr. Eun Young Yu emphasized that these findings provide the inaugural in vivo evidence that polymerase α/primase participates in both telomeric DNA synthesis and protection.
The ramifications of this research stretch beyond basic biology, offering implications for understanding and treating telomere biology disorders. Coats plus syndrome, a rare premature aging disease manifesting in multisystem damage including ocular and skeletal abnormalities, exemplifies this. Patients with Coats plus exhibit shorter telomeres than their chronological age would predict, often linked to mutations within CST subunits. Dr. Lue postulates such mutations may disrupt CST-PP interactions, undermining telomere stability and contributing to the disease phenotype. This insight paves pathways for exploring targeted molecular therapies aimed at restoring or compensating CST-PP function in afflicted individuals.
Moreover, telomerase dysregulation underpins myriad cancers, as unlimited proliferative capacity necessitates telomere extension to counteract replicative senescence. Mutations that enhance telomerase activity are frequently observed across diverse tumor types. Consequently, modulating CST protein function emerges as a promising therapeutic strategy. By fine-tuning CST’s control over telomerase and telomere protection, it may be possible to blunt cancer cell proliferation, either alone or synergistically with existing treatments. Additionally, manipulating CST pathways could overcome resistance mechanisms that compromise the efficacy of certain chemotherapies, marking these proteins as compelling drug targets.
The research benefits from robust funding and collaborative endeavors, reflecting the complexity and cross-disciplinary nature of telomere biology. Support from the National Science Foundation, the National Institutes of Health, Boehringer Ingelheim Fonds, and Spanish research agencies underpins this multifaceted approach. The study encapsulates a critical advance in revealing how protein partnerships coordinate to regulate telomere dynamics, blending structural biology, genetics, and cell biology to resolve longstanding questions.
Ultimately, this work establishes a refined molecular framework for telomere maintenance, crucial for cell survival and organismal health. By elucidating the interplay between the CST complex and DNA polymerase α/primase, it disentangles the mechanisms ensuring that telomerase activity is precisely controlled and telomeres are protected. These discoveries spotlight a previously concealed dimension of chromosome end biology and set the stage for novel clinical interventions targeting age-related diseases and cancers through modulation of telomere regulation.
Subject of Research: Telomere maintenance, protein interactions regulating telomerase, chromosome end protection
Article Title: Not specified in content
News Publication Date: April 17, 2022
Web References:
- Nucleic Acids Research Full Article
- Earlier Work on CST and Polymerase α activity
- Sandra and Edward Meyer Cancer Center
- Spanish National Cancer Research Centre
- Dr. Neal Lue Profile
- Dr. Eun Young Yu Profile
References:
- Study published in Nucleic Acids Research, April 17, 2022; DOI: 10.1093/nar/gkaf245
- Previous research in Nature Communications on CST stimulation of polymerase α
Image Credits: Hesed M. Padilla-Nash and Thomas Ried, National Cancer Institute
Keywords: Wild type cells, Drug targets, Gene targeting, Basic research, Drug research, Cancer research
