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SMARCAL1 maintains telomere integrity during DNA replication.
Poole LA, Zhao R, Glick GG, Lovejoy CA, Eischen CM, Cortez D
(2015) Proc Natl Acad Sci U S A 112: 14864-9
MeSH Terms: Animals, Chromosomes, Human, DNA Damage, DNA Helicases, DNA Replication, HeLa Cells, Humans, Mice, Recombination, Genetic, Telomere, Telomere Homeostasis
Show Abstract · Added February 4, 2016
The SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) DNA translocase is one of several related enzymes, including ZRANB3 (zinc finger, RAN-binding domain containing 3) and HLTF (helicase-like transcription factor), that are recruited to stalled replication forks to promote repair and restart replication. These enzymes can perform similar biochemical reactions such as fork reversal; however, genetic studies indicate they must have unique cellular activities. Here, we present data showing that SMARCAL1 has an important function at telomeres, which present an endogenous source of replication stress. SMARCAL1-deficient cells accumulate telomere-associated DNA damage and have greatly elevated levels of extrachromosomal telomere DNA (C-circles). Although these telomere phenotypes are often found in tumor cells using the alternative lengthening of telomeres (ALT) pathway for telomere elongation, SMARCAL1 deficiency does not yield other ALT phenotypes such as elevated telomere recombination. The activity of SMARCAL1 at telomeres can be separated from its genome-maintenance activity in bulk chromosomal replication because it does not require interaction with replication protein A. Finally, this telomere-maintenance function is not shared by ZRANB3 or HLTF. Our results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes.
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11 MeSH Terms
Blood Telomere Length Attrition and Cancer Development in the Normative Aging Study Cohort.
Hou L, Joyce BT, Gao T, Liu L, Zheng Y, Penedo FJ, Liu S, Zhang W, Bergan R, Dai Q, Vokonas P, Hoxha M, Schwartz J, Baccarelli A
(2015) EBioMedicine 2: 591-6
MeSH Terms: Aged, Aged, 80 and over, Aging, Biomarkers, Tumor, Cohort Studies, Humans, Leukocytes, Longitudinal Studies, Male, Middle Aged, Neoplasms, Prospective Studies, Telomere, Telomere Homeostasis, Telomere Shortening
Show Abstract · Added May 6, 2016
BACKGROUND - Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence.
METHODS - We included 792 Normative Aging Study participants with 1-4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis.
FINDINGS - Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (pdifference = 0.017); all participants had similar age-adjusted BTL 8-14 years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p = 0.003) and four (p = 0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR = 1.79, p = 0.03), and longer BTL measured ≤ 4 years pre-diagnosis with any (OR = 3.27, p < 0.001) and prostate cancers (OR = 6.87, p < 0.001).
INTERPRETATION - Age-related BTL attrition was faster in cancer cases but their age-adjusted BTL attrition began decelerating as diagnosis approached. This may explain prior inconsistencies and help develop BTL as a cancer detection biomarker.
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Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.
Machiela MJ, Hsiung CA, Shu XO, Seow WJ, Wang Z, Matsuo K, Hong YC, Seow A, Wu C, Hosgood HD, Chen K, Wang JC, Wen W, Cawthon R, Chatterjee N, Hu W, Caporaso NE, Park JY, Chen CJ, Kim YH, Kim YT, Landi MT, Shen H, Lawrence C, Burdett L, Yeager M, Chang IS, Mitsudomi T, Kim HN, Chang GC, Bassig BA, Tucker M, Wei F, Yin Z, An SJ, Qian B, Lee VH, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Kim JH, Gao YT, Tsai YH, Jung YJ, Guo H, Hu Z, Hutchinson A, Wang WC, Klein RJ, Chung CC, Oh IJ, Chen KY, Berndt SI, Wu W, Chang J, Zhang XC, Huang MS, Zheng H, Wang J, Zhao X, Li Y, Choi JE, Su WC, Park KH, Sung SW, Chen YM, Liu L, Kang CH, Hu L, Chen CH, Pao W, Kim YC, Yang TY, Xu J, Guan P, Tan W, Su J, Wang CL, Li H, Sihoe AD, Zhao Z, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Kohno T, Kweon SS, Chen CY, Vermeulen RC, Wu J, Lim WY, Chen KC, Chow WH, Ji BT, Chan JK, Chu M, Li YJ, Yokota J, Li J, Chen H, Xiang YB, Yu CJ, Kunitoh H, Wu G, Jin L, Lo YL, Shiraishi K, Chen YH, Lin HC, Wu T, Wong MP, Wu YL, Yang PC, Zhou B, Shin MH, Fraumeni JF, Zheng W, Lin D, Chanock SJ, Rothman N, Lan Q
(2015) Int J Cancer 137: 311-9
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, China, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Hong Kong, Humans, Japan, Lung Neoplasms, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Prospective Studies, Republic of Korea, Risk Factors, Singapore, Smoking, Taiwan, Telomere, Telomere Homeostasis
Show Abstract · Added April 3, 2018
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.
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MeSH Terms
Normal telomere length maintenance in Saccharomyces cerevisiae requires nuclear import of the ever shorter telomeres 1 (Est1) protein via the importin alpha pathway.
Hawkins C, Friedman KL
(2014) Eukaryot Cell 13: 1036-50
MeSH Terms: Active Transport, Cell Nucleus, Amino Acid Sequence, Cell Nucleus, Molecular Sequence Data, Nuclear Localization Signals, Nucleocytoplasmic Transport Proteins, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomerase, Telomere Homeostasis, beta Karyopherins
Show Abstract · Added January 20, 2015
The Est1 (ever shorter telomeres 1) protein is an essential component of yeast telomerase, a ribonucleoprotein complex that restores the repetitive sequences at chromosome ends (telomeres) that would otherwise be lost during DNA replication. Previous work has shown that the telomerase RNA component (TLC1) transits through the cytoplasm during telomerase biogenesis, but mechanisms of protein import have not been addressed. Here we identify three nuclear localization sequences (NLSs) in Est1p. Mutation of the most N-terminal NLS in the context of full-length Est1p reduces Est1p nuclear localization and causes telomere shortening-phenotypes that are rescued by fusion with the NLS from the simian virus 40 (SV40) large-T antigen. In contrast to that of the TLC1 RNA, Est1p nuclear import is facilitated by Srp1p, the yeast homolog of importin α. The reduction in telomere length observed at the semipermissive temperature in a srp1 mutant strain is rescued by increased Est1p expression, consistent with a defect in Est1p nuclear import. These studies suggest that at least two nuclear import pathways are required to achieve normal telomere length homeostasis in yeast.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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12 MeSH Terms
Pif1 family helicases suppress genome instability at G-quadruplex motifs.
Paeschke K, Bochman ML, Garcia PD, Cejka P, Friedman KL, Kowalczykowski SC, Zakian VA
(2013) Nature 497: 458-62
MeSH Terms: Base Sequence, Conserved Sequence, DNA Damage, DNA Helicases, Epigenesis, Genetic, Evolution, Molecular, G-Quadruplexes, Gene Silencing, Genetic Complementation Test, Genomic Instability, Humans, Molecular Sequence Data, Mutation Rate, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomere Homeostasis
Show Abstract · Added March 7, 2014
The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.
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16 MeSH Terms
Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.
Lan Q, Cawthon R, Gao Y, Hu W, Hosgood HD, Barone-Adesi F, Ji BT, Bassig B, Chow WH, Shu X, Cai Q, Xiang Y, Berndt S, Kim C, Chanock S, Zheng W, Rothman N
(2013) PLoS One 8: e59230
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Adult, Aged, Case-Control Studies, China, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Leukocytes, Mononuclear, Lung Neoplasms, Membrane Proteins, Middle Aged, Neoplasm Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Prospective Studies, Risk, Telomerase, Telomere, Telomere Homeostasis
Show Abstract · Added March 18, 2014
A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations.
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Telomerase deficiency does not alter bleomycin-induced fibrosis in mice.
Degryse AL, Xu XC, Newman JL, Mitchell DB, Tanjore H, Polosukhin VV, Jones BR, McMahon FB, Gleaves LA, Phillips JA, Cogan JD, Blackwell TS, Lawson WE
(2012) Exp Lung Res 38: 124-34
MeSH Terms: Airway Remodeling, Animals, Antibiotics, Antineoplastic, Bleomycin, Collagen, Epithelial Cells, Female, Idiopathic Pulmonary Fibrosis, Leukocytes, Lung, Male, Mice, Mice, Inbred C57BL, Mutation, Pneumonia, Pulmonary Alveoli, RNA, Telomerase, Telomere Homeostasis, Telomere Shortening
Show Abstract · Added March 5, 2014
Idiopathic pulmonary fibrosis (IPF) is characterized by interstitial lung infiltrates, dyspnea, and progressive respiratory failure. Reports linking telomerase mutations to familial interstitial pneumonia (FIP) suggest that telomerase activity and telomere length maintenance are important in disease pathogenesis. To investigate the role of telomerase in lung fibrotic remodeling, intratracheal bleomycin was administered to mice deficient in telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) and to wild-type controls. TERT-deficient and TERC-deficient mice were interbred to the F6 and F4 generation, respectively, when they developed skin manifestations and infertility. Fibrosis was scored using a semiquantitative scale and total lung collagen was measured using a hydroxyprolinemicroplate assay. Telomere lengths were measured in peripheral blood leukocytes and isolated type II alveolar epithelial cells (AECs). Telomerase activity in type II AECs was measured using a real-time polymerase chain reaction (PCR)-based system. Following bleomycin, TERT-deficient and TERC-deficient mice developed an equivalent inflammatory response and similar lung fibrosis (by scoring of lung sections and total lung collagen content) compared to controls, a pattern seen in both early (F1) and later (F6 TERT and F4 TERC) generations. Telomere lengths were reduced in peripheral blood leukocytes and isolated type II AECs from F6 TERT-deficient and F4 TERC-deficient mice compared to controls. Telomerase deficiency in a murine model leads to telomere shortening, but does not predispose to enhanced bleomycin-induced lung fibrosis. Additional genetic or environmental factors may be necessary for development of fibrosis in the presence of telomerase deficiency.
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20 MeSH Terms
A mutation in the catalytic subunit of yeast telomerase alters primer-template alignment while promoting processivity and protein-DNA binding.
Bairley RC, Guillaume G, Vega LR, Friedman KL
(2011) J Cell Sci 124: 4241-52
MeSH Terms: Catalytic Domain, DNA, DNA Primers, Glutamic Acid, Mutation, Protein Binding, Saccharomyces cerevisiae Proteins, Telomerase, Telomere, Telomere Homeostasis, Templates, Genetic
Show Abstract · Added March 7, 2014
Telomerase is a ribonucleoprotein complex that is required for maintenance of linear chromosome ends (telomeres). In yeast, the Est2 protein reverse transcribes a short template region of the TLC1 RNA using the chromosome terminus to prime replication. Yeast telomeres contain heterogeneous G(1-3)T sequences that arise from incomplete reverse transcription of the TLC1 template and alignment of the DNA primer at multiple sites within the template region. We have previously described mutations in the essential N-terminal TEN domain of Est2p that alter telomere sequences. Here, we demonstrate that one of these mutants, glutamic acid 76 to lysine (est2-LT(E76K)), restricts possible alignments between the DNA primer and the TLC1 template. In addition, this mutant exhibits increased processivity in vivo. Within the context of the telomerase enzyme, the Est2p TEN domain is thought to contribute to enzyme processivity by mediating an anchor-site interaction with the DNA primer. We show that binding of the purified TEN domain (residues 1-161) to telomeric DNA is enhanced by the E76K mutation. These results support the idea that the anchor-site interaction contributes to telomerase processivity and suggest a role for the anchor site of yeast telomerase in mediating primer-template alignment within the active site.
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11 MeSH Terms