A5068271598- Telomeres, Telomerase, and Senescence
- DNA Repair Mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Cancer-related Molecular Pathways
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Chromosomal and Genetic Variations
- Cancer Genomics and Diagnostics
- Microtubule and mitosis dynamics
- Chronic Lymphocytic Leukemia Research
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- Pluripotent Stem Cells Research
- Genomic variations and chromosomal abnormalities
- RNA regulation and disease
- Glycosylation and Glycoproteins Research
- Sirtuins and Resveratrol in Medicine
- PARP inhibition in cancer therapy
- Ocular Oncology and Treatments
- Mitochondrial Function and Pathology
- Acute Lymphoblastic Leukemia research
- Genetic factors in colorectal cancer
- Microplastics and Plastic Pollution
- Circadian rhythm and melatonin
- Viral Infectious Diseases and Gene Expression in Insects
National Institute on Aging
2014-2023
National Institutes of Health
2012-2023
Institute on Aging
2021-2023
Institute of Aging
2019
Laboratory of Molecular Genetics
2015
United States Department of Health and Human Services
2014
Tufts University
2011
Universidade de São Paulo
2011
Towson University
2011
Oak Ridge National Laboratory
2004-2009
8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) are among the most common oxidative DNA lesions substrates for 8-oxoguanine glycosylase (OGG1)–initiated base excision repair (BER). Mammalian telomeres consist of triple guanine repeats subject to damage. Here, we investigated impact damage its by OGG1 on telomere integrity in mice. The mouse cells were analyzed quantitative fluorescence situ hybridization (telomere–FISH), chromosome orientation–FISH...
SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. also telomeric protein TRF2 human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure TRF2-binding motif (SLX4TBM) complex TRFH domain (TRF2TRFH) and map SLX1, XPF, MUS81. recognizes a unique HxLxP on via peptide-binding site its domain. Telomeric localization associated nucleases depend SLX4-endonuclease SLX4-TRF2 levels TRF2....
Poly(ADP-ribose)polymerase 1 (PARP1) is well characterized for its role in base excision repair (BER), where it activated by and binds to DNA breaks catalyzes the poly(ADP-ribosyl)ation of several substrates involved damage repair. Here we demonstrate that PARP1 associates with telomere repeat binding factor 2 (TRF2) capable TRF2, which affects TRF2 telomeric DNA. Immunostaining interphase cells or metaphase spreads shows detected sporadically at normal telomeres, but appears preferentially...
The transcription factor B-Myb is present in all proliferating cells, and mice engineered to remove this gene, embryos die utero just after implantation due inner cell mass defects. This lethal phenotype has generally been attributed a proliferation defect the cycle phase of G1.In study, we show that major murine embryonic stem (mES) cells occurs G2/M. Specifically, knockdown by short-hairpin RNAs results delayed transit through G2/M, severe mitotic spindle centrosome defects, polyploidy....
Article16 September 2020Open Access Source DataTransparent process Re-equilibration of imbalanced NAD metabolism ameliorates the impact telomere dysfunction Chongkui Sun Biomedical Research Center, National Institute on Aging/National Institutes Health, Baltimore, MD, USA Search for more papers by this author Kun Wang Amanda J Stock Yi Gong Tyler G Demarest Beimeng Yang Neelam Giri orcid.org/0000-0001-7353-1863 Clinical Genetics Branch, Division Cancer Epidemiology and Genetics, Institute,...
Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage secrete factors that promote atherosclerotic plaque vulnerability disease. Here, we report increased levels activity of dipeptidyl peptidase 4 (DPP4), a serine protease, senescent VSMCs. Analysis conditioned media from VSMCs revealed unique senescence-associated secretory phenotype (SASP) signature comprising many complement coagulation factors; silencing or inhibiting DPP4 reduced these...
Telomerase is a ribonucleoprotein containing an essential telomerase RNA template and reverse transcriptase (TERT) that maintains telomeres. The dosage requirements for mammalian TERT in telomere length homeostasis are not known, but of importance cellular senescence, stem cell renewal, cancer. Here, we characterize maintenance function upon successive breeding mice deficient mTert . These studies reveal unique requirement by TERT; despite haploinsufficiency the long telomeres, +/- retain...
The Cdc14 dual-specificity phosphatases regulate key events in the eukaryotic cell cycle. However, little is known about function of mammalian CDC14B family members. Here, we demonstrate that subcellular localization protein cycle regulated. can bind, bundle, and stabilize microtubules vitro independently its catalytic activity. Basic amino acid residues within nucleolar targeting domain are important for both retaining nucleolus preventing microtubule bundling. Overexpression resulted...
SLX4 assembles a toolkit of endonucleases SLX1, MUS81 and XPF, which is recruited to telomeres via direct interaction with TRF2.Telomeres present an inherent obstacle for DNA replication repair due their high propensity form branched intermediates.Here we provide novel insight into the mechanism regulation complex in telomere preservation.SLX4 associates throughout cell cycle, peaking late S phase under genotoxic stress.Disruption SLX4's TRF2 or SLX1 SLX1's nuclease activity independently...
Base excision repair (BER) handles many forms of endogenous DNA damage, and apurinic/apyrimidinic endonuclease 1 (APE1) is central to this process. Deletion both alleles APE1 (a.k.a. Apex1) in mice leads embryonic lethality, deficiency cells can promote cell death. Unlike most other BER proteins, expression inversely correlated with cellular senescence primary human fibroblasts. Depletion via shRNA induced normal BJ fibroblasts, a phenotype that was not seen counterpart expressing...
Telomeres are chromosome end structures and essential for maintenance of genome stability. Highly repetitive telomere sequences appear to be susceptible oxidative stress-induced damage. Oxidation may therefore have a severe impact on integrity function. A wide spectrum pyrimidine-derivatives has been reported, including thymine glycol (Tg), that primarily removed by DNA glycosylase, Endonuclease III-like protein 1 (Nth1). Here, we investigate the effect Nth1 deficiency in mice. null...
Summary In a previous whole exome sequencing of patients from 41 families with Hodgkin lymphoma, we identified two distinct heterozygous rare coding variants in POT 1 (D224N and Y36H), both highly conserved region the gene. D224N mutant did not bind to single‐stranded telomere oligonucleotide vitro suggesting mutation perturbs 1's ability telomeric G‐rich overhang. Human HT 1080 cells expressing lymphoblastoid carrying Y36H showed increased length fragility comparison wild type cells. This...
Vaults and telomerase are ribonucleoprotein (RNP) particles that share a common protein subunit, TEP1. Although its role in either complex has not yet been defined, TEP1 shown to interact with the mouse RNA several of human vault RNAs yeast three-hybrid assay. An mTep1(-/-) was previously generated which resulted no apparent change telomere length or activity six generations mTep1-deficient mice. Here we show levels association RNP also unaffected vaults purified from livers mice appear...
Prolonged growth of murine embryonic stem (ES) cells lacking the telomerase reverse transcriptase, mTert , results in a loss telomere DNA and an increased incidence end-to-end fusions aneuploidy. Furthermore, only one copy also shortening intermediate between wild-type (wt) -null ES [Liu, Y., Snow, B. E., Hande, M. P., Yeung, D., Erdmann, N. J., Wakeham, A., Itie, Siderovski, D. Lansdorp, P. M., Robinson, O. & Harrington, L. (2000) Curr. Biol. 10, 1459–1462]. Unexpectedly, although...