About
Neal F. Lue is a researcher whose work primarily focuses on telomere biology, chromosome end protection, and DNA repair mechanisms. His research explores the molecular architecture and interactions of nucleic acid-protein complexes at chromosome ends, with particular attention to telomerase mechanisms, telomere maintenance, and the evolution of telomere-binding proteins in fungi. Lue has contributed to understanding how telomere-binding proteins, such as Cdc13 and Pot1, recognize and regulate telomere structures, and how these processes are involved in genome stability and cellular aging. His work also investigates the roles of recombination and repair proteins in telomere dynamics, including the formation of alternative lengthening of telomeres (ALT) pathways, and the impact of telomere maintenance on genome integrity and disease states.
Research topics
- Cell biology
- Genetics
- Biology
Selected publications
Nucleic Acids Research · 2025-03-19 · 1 citations
articleOpen accessSenior authorPolα/primase (PP), the polymerase that initiates DNA synthesis at replication origins, also completes the task of genome duplication by synthesizing the telomere C-strand under the control of the CTC1/CDC13-STN1-TEN1 (CST) complex. Using cryo-electron microscopy (cryo-EM) structures of the human CST-Polα/primase-DNA complex as guides in conjunction with AlphaFold modeling, we identified structural elements in yeast CST and PP that promote complex formation. Mutating these structures in Candida glabrata Stn1, Ten1, Pri1, and Pri2 abrogated the stimulatory activity of CST on PP in vitro, supporting the functional relevance of the physical contacts in cryo-EM structures as well as the conservation of mechanisms between yeast and humans. Introducing these mutations into C. glabrata yielded two distinct groups of mutants. One group exhibited progressive, telomerase-dependent telomere elongation without evidence of DNA damage. The other manifested slow growth, telomere length heterogeneity, single-stranded DNA accumulation and elevated C-circles, which are indicative of telomere deprotection. These telomere deprotection phenotypes are altered or suppressed by mutations in multiple DNA damage response (DDR) and DNA repair factors. We conclude that in yeast, the telomerase inhibition and telomere protection function previously ascribed to the CST complex are mediated jointly by both CST and Polα/primase, highlighting the critical importance of a replicative DNA polymerase in telomere regulation.
PLoS Genetics · 2024-12-09 · 1 citations
articleOpen accessSenior authorCorrespondingTRF2 is an essential and conserved double-strand telomere binding protein that stabilizes chromosome ends by suppressing DNA damage response and aberrant DNA repair. Herein we investigated the mechanisms and functions of the Trf2 ortholog in the basidiomycete fungus Ustilago maydis, which manifests strong resemblances to metazoans with regards to the telomere and DNA repair machinery. We showed that UmTrf2 binds to Blm in vitro and inhibits Blm-mediated unwinding of telomeric DNA substrates. Consistent with a similar inhibitory activity in vivo, over-expression of Trf2 induces telomere shortening, just like deletion of blm, which is required for efficient telomere replication. While the loss of Trf2 engenders growth arrest and multiple telomere aberrations, these defects are fully suppressed by the concurrent deletion of blm or mre11 (but not other DNA repair factors). Over-expression of Blm alone triggers aberrant telomere recombination and the accumulation of aberrant telomere structures, which are blocked by concurrent Trf2 over-expression. Together, these findings highlight the suppression of Blm as a key protective mechanism of Trf2. Notably, U. maydis harbors another double-strand telomere-binding protein (Tay1), which promotes Blm activity to ensure efficient replication. We found that deletion of tay1 partially suppresses the telomere aberration of Trf2-depleted cells. Our results thus point to opposing regulation of Blm helicase by telomere proteins as a strategy for optimizing both telomere maintenance and protection. We also show that aberrant transcription of both telomere G- and C-strand is a recurrent phenotype of telomere mutants, underscoring another potential similarity between double strand breaks and de-protected telomeres.
Association of phenotypic frailty and hand grip strength with telomere length in SLE
Lupus Science & Medicine · 2024-03-01 · 7 citations
articleOpen accessOBJECTIVE: Frailty and objective hand grip strength (one of the components of the frailty phenotype) are both risk factors for worse health outcomes in SLE. Whether telomere length, an established cellular senescence marker, is a biologic correlate of the frailty phenotype and hand grip strength in patients with SLE is not clear. First, we aimed to evaluate differences in telomere length between frail and non-frail women with SLE and then assessed whether frailty or hand grip strength is differentially associated with telomere length after adjusting for relevant confounders. METHODS: Women ≥18 years of age with validated SLE enrolled at a single medical centre. Fried frailty status (which includes hand grip strength), clinical characteristics and telomere length were assessed cross-sectionally. Differences between frail and non-frail participants were evaluated using Fisher's exact or Wilcoxon rank-sum tests. The associations between frailty and hand grip strength and telomere length were determined using linear regression. RESULTS: Of the 150 enrolled participants, 131 had sufficient data for determination of frailty classification; 26% were frail with a median age of 45 years. There was a non-significant trend towards shorter telomere length in frail versus non-frail participants (p=0.07). Hand grip strength was significantly associated with telomere length (beta coefficient 0.02, 95% CI 0.004, 0.04), including after adjustment for age, SLE disease activity and organ damage, and comorbidity (beta coefficient 0.02, 95% CI 0.002, 0.04). CONCLUSIONS: Decreased hand grip strength, but not frailty, was independently associated with shortened telomere length in a cohort of non-elderly women with SLE. Frailty in this middle-aged cohort may be multifactorial rather than strictly a manifestation of accelerated ageing.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-20
preprintSenior authorCorrespondingAbstract Polα/primase, the polymerase that initiates DNA synthesis at replication origins, also completes the task of genome duplication by synthesizing the telomere C-strand under the control of the CST complex. Using cryo-EM structures of the human CST-Polα/primase-DNA complex as guides in conjunction with AlphaFold modeling, we identified structural elements in yeast CST and Polα/primase that promote complex formation. Mutating these structures in Candida glabrata Stn1, Ten1, Pri1 and Pri2 abrogated the stimulatory activity of CST on Polα/primase in vitro, supporting the functional relevance of the physical contacts in cryo-EM structures as well as the conservation of mechanisms between yeast and humans. Introducing these mutations into C. glabrata yielded two distinct groups of mutants. One group exhibited progressive, telomerase-dependent telomere elongation without evidence of DNA damage. The other manifested slow growth, telomere length heterogeneity, ssDNA accumulation and elevated C-circles, which are indicative of telomere deprotection. These telomere deprotection phenotypes are altered or suppressed by mutations in multiple DDR and DNA repair factors. We conclude that in yeast, the telomerase inhibition and telomere protection function previously ascribed to the CST complex are mediated jointly by both CST and Polα/primase, highlighting the critical importance of a replicative DNA polymerase in telomere regulation.
Nature Communications · 2023 · 22 citations
- Biology
- Cell biology
- Genetics
Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.
bioRxiv (Cold Spring Harbor Laboratory) · 2023-04-17
preprintOpen accessSenior authorCorrespondingAbstract TRF2 is an essential and conserved double-strand telomere binding protein that stabilizes chromosome ends by suppressing DNA damage response and aberrant DNA repair. Herein we investigated the mechanisms and functions of the Trf2 ortholog in the basidiomycete fungus Ustilago maydis, which manifests strong resemblances to metazoans with regards to the telomere and DNA repair machinery. We showed that Um Trf2 binds to Blm in vitro and inhibits Blm-mediated unwinding of telomeric DNA substrates. Consistent with a similar inhibitory activity in vivo , over-expression of Trf2 induces telomere shortening, just like deletion of blm, which is required for efficient telomere replication. While the loss of Trf2 engenders growth arrest and multiple telomere aberrations, these defects are fully suppressed by the concurrent deletion of blm or mre11 (but not other DNA repair factors). Over-expression of Blm alone triggers aberrant telomere recombination and the accumulation of aberrant telomere structures, which are blocked by concurrent Trf2 over-expression. Together, these findings highlight the suppression of Blm as a key protective mechanism of Trf2. Notably, U. maydis harbors another double-strand telomere-binding protein (Tay1), which promotes Blm activity to ensure efficient replication. We found that deletion of tay1 partially suppresses the telomere aberration of Trf2-depleted cells. Our results thus point to opposing regulation of Blm helicase by telomere proteins as a strategy for optimizing both telomere maintenance and protection. We also show that aberrant transcription of both telomere G- and C-strand is a recurrent phenotype of telomere mutants, underscoring another potential similarity between double strand breaks and de-protected telomeres. Author Summary The ends of linear chromosomes are protected from abnormal repair by a collection of telomere proteins. One protein that plays an especially prominent role is TRF2, which binds to double-stranded telomere repeats. In this study, we analyzed the mechanisms and functions of Trf2 in a yeast-like fungus named Ustilago maydis , which manifests a high degree of similarity to animal cells with respect to telomere regulation. We showed that Trf2 binds directly to a conserved DNA helicase called Blm and inhibits the ability of Blm to unwind telomeric DNA in a purified, cell-free reaction. We also used over-expression and depletion of either Trf2 or Blm or both to demonstrate an inhibitory effect of Trf2 on Blm function in vivo . For example, depletion of Trf2 triggers Blm-dependent telomere aberrations and cell death. Interestingly, another double-strand telomere binding protein named Tay1 was found to stimulate Blm activity to promote telomere replication. Together, our results indicate that U. maydis optimizes Blm function through opposing regulation of its activity via distinct telomere proteins. We also detected high levels of abnormal transcripts that correspond to both strands of telomeres in a variety of telomere mutants, suggesting that de-protected telomeres are permissive substrates for the transcription apparatus.
Nucleic Acids Research · 2023-01-11 · 4 citations
articleOpen accessThe CST complex is a key player in telomere replication and stability, which in yeast comprises Cdc13, Stn1 and Ten1. While Stn1 and Ten1 are very well conserved across species, Cdc13 does not resemble its mammalian counterpart CTC1 either in sequence or domain organization, and Cdc13 but not CTC1 displays functions independently of the rest of CST. Whereas the structures of human CTC1 and CST have been determined, the molecular organization of Cdc13 remains poorly understood. Here, we dissect the molecular architecture of Candida glabrata Cdc13 and show how it regulates binding to telomeric sequences. Cdc13 forms dimers through the interaction between OB-fold 2 (OB2) domains. Dimerization stimulates binding of OB3 to telomeric sequences, resulting in the unfolding of ssDNA secondary structure. Once bound to DNA, Cdc13 prevents the refolding of ssDNA by mechanisms involving all domains. OB1 also oligomerizes, inducing higher-order complexes of Cdc13 in vitro. OB1 truncation disrupts these complexes, affects ssDNA unfolding and reduces telomere length in C. glabrata. Together, our results reveal the molecular organization of C. glabrata Cdc13 and how this regulates the binding and the structure of DNA, and suggest that yeast species evolved distinct architectures of Cdc13 that share some common principles.
bioRxiv (Cold Spring Harbor Laboratory) · 2023-02-11 · 1 citations
preprintOpen accessTelomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.
Nature Structural & Molecular Biology · 2023-07-01 · 14 citations
reviewOpen access1st authorCorrespondingPLoS Genetics · 2022-05-19 · 8 citations
articleOpen accessSenior authorCorrespondingThe telomere G-strand binding protein Pot1 plays multifaceted roles in telomere maintenance and protection. We examined the structure and activities of Pot1 in Ustilago maydis, a fungal model that recapitulates key features of mammalian telomere regulation. Compared to the well-characterized primate and fission yeast Pot1 orthologs, UmPot1 harbors an extra N-terminal OB-fold domain (OB-N), which was recently shown to be present in most metazoans. UmPot1 binds directly to Rad51 and regulates the latter's strand exchange activity. Deleting the OB-N domain, which is implicated in Rad51-binding, caused telomere shortening, suggesting that Pot1-Rad51 interaction facilitates telomere maintenance. Depleting Pot1 through transcriptional repression triggered growth arrest as well as rampant recombination, leading to multiple telomere aberrations. In addition, telomere repeat RNAs transcribed from both the G- and C-strand were dramatically up-regulated, and this was accompanied by elevated levels of telomere RNA-DNA hybrids. Telomere abnormalities of pot1-deficient cells were suppressed, and cell viability was restored by the deletion of genes encoding Rad51 or Brh2 (the BRCA2 ortholog), indicating that homology-directed repair (HDR) proteins are key mediators of telomere aberrations and cellular toxicity. Together, these observations underscore the complex physical and functional interactions between Pot1 and DNA repair factors, leading to context-dependent and dichotomous effects of HDR proteins on telomere maintenance and protection.
Recent grants
NSF · $796k · 2018–2022
Mechanisms and Evolution of the Telomere Protective Complex Cdc13-Stn1-Ten1
NSF · $845k · 2012–2017
Telomere terminal extension and replication: mechanisms and links to DNA repair
NIH · $2.9M · 2014–2025
NIH · $1.2M · 2010
NIH · $3.0M · 2012
Frequent coauthors
- 113 shared
Eun Young Yu
Hearst (United States)
- 62 shared
William K. Holloman
Weill Cornell Medicine
- 54 shared
Syed Zahid
Hearst (United States)
- 51 shared
Jeanette Sutherland
Cornell University
- 49 shared
Min Hsu
New York University
- 48 shared
Sarah Aloe
Cornell University
- 33 shared
Olga Steinberg‐Neifach
Cornell University
- 27 shared
Ming Lei
Shanghai Jiao Tong University
Education
- 1991
MD, PhD, Cell Biology
Stanford University School of Medicine
- 1984
BS, Biology
Johns Hopkins University
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