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5. ALTercations at telomeres: stress, recombination and extrachromosomal affairs.

Author

Loe, Taylor K., Denchi, Eros Lazzerini, Tricola, Gianna M., and Azeroglu, Benura

Subjects
*TELOMERES, *EXTRACHROMOSOMAL DNA, *DNA repair
Abstract

Approximately 15% of human cancers depend on the alternative lengthening of telomeres (ALT) pathway to maintain telomeres and proliferate. Telomeres that are elongated using ALT display unique features raising the exciting prospect of tailored cancer therapies. ALT-mediated telomere elongation shares several features with recombination-based DNA repair. Strikingly, cells that use the ALT pathway display abnormal levels of replication stress at telomeres and accumulate abundant extrachromosomal telomeric DNA. In this review, we examine recent findings that shed light on the ALT mechanisms and the strategies currently available to suppress this telomere elongation mechanism. [ABSTRACT FROM AUTHOR]

Published
2023
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8. A two-step mechanism for TRF2-mediated chromosome-end protection

Author

Okamoto, Keiji, Bartocci, Cristina, Ouzounov, Iliana, Diedrich, Jolene K., Yates, III, John R., and Denchi, Eros Lazzerini

Subjects
Binding proteins -- Observations, DNA damage -- Research, Telomeres -- Properties, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Mammalian telomeres repress DNA-damage activation at natural chromosome ends by recruiting specific inhibitors of the DNA-damage machinery that form a protective complex termed shelterin. Within this complex, TRF2 (also known [...]

Published
2013
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10. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, Chen, primary, Stoma, Svetlana, additional, Lotta, Luca A., additional, Warner, Sophie, additional, Albrecht, Eva, additional, Allione, Alessandra, additional, Arp, Pascal P., additional, Broer, Linda, additional, Buxton, Jessica L., additional, Da Silva Couto Alves, Alexessander, additional, Deelen, Joris, additional, Fedko, Iryna O., additional, Gordon, Scott D., additional, Jiang, Tao, additional, Karlsson, Robert, additional, Kerrison, Nicola, additional, Loe, Taylor K., additional, Mangino, Massimo, additional, Milaneschi, Yuri, additional, Miraglio, Benjamin, additional, Pervjakova, Natalia, additional, Russo, Alessia, additional, Surakka, Ida, additional, van der Spek, Ashley, additional, Verhoeven, Josine E., additional, Amin, Najaf, additional, Beekman, Marian, additional, Blakemore, Alexandra I., additional, Canzian, Federico, additional, Hamby, Stephen E., additional, Hottenga, Jouke-Jan, additional, Jones, Peter D., additional, Jousilahti, Pekka, additional, Mägi, Reedik, additional, Medland, Sarah E., additional, Montgomery, Grant W., additional, Nyholt, Dale R., additional, Perola, Markus, additional, Pietiläinen, Kirsi H., additional, Salomaa, Veikko, additional, Sillanpää, Elina, additional, Suchiman, H. Eka, additional, van Heemst, Diana, additional, Willemsen, Gonneke, additional, Agudo, Antonio, additional, Boeing, Heiner, additional, Boomsma, Dorret I., additional, Chirlaque, Maria-Dolores, additional, Fagherazzi, Guy, additional, Ferrari, Pietro, additional, Franks, Paul, additional, Gieger, Christian, additional, Eriksson, Johan Gunnar, additional, Gunter, Marc, additional, Hägg, Sara, additional, Hovatta, Iiris, additional, Imaz, Liher, additional, Kaprio, Jaakko, additional, Kaaks, Rudolf, additional, Key, Timothy, additional, Krogh, Vittorio, additional, Martin, Nicholas G., additional, Melander, Olle, additional, Metspalu, Andres, additional, Moreno, Concha, additional, Onland-Moret, N. Charlotte, additional, Nilsson, Peter, additional, Ong, Ken K., additional, Overvad, Kim, additional, Palli, Domenico, additional, Panico, Salvatore, additional, Pedersen, Nancy L., additional, Penninx, Brenda W.J. H., additional, Quirós, J. Ramón, additional, Jarvelin, Marjo Riitta, additional, Rodríguez-Barranco, Miguel, additional, Scott, Robert A., additional, Severi, Gianluca, additional, Slagboom, P. Eline, additional, Spector, Tim D., additional, Tjonneland, Anne, additional, Trichopoulou, Antonia, additional, Tumino, Rosario, additional, Uitterlinden, André G., additional, van der Schouw, Yvonne T., additional, van Duijn, Cornelia M., additional, Weiderpass, Elisabete, additional, Denchi, Eros Lazzerini, additional, Matullo, Giuseppe, additional, Butterworth, Adam S., additional, Danesh, John, additional, Samani, Nilesh J., additional, Wareham, Nicholas J., additional, Nelson, Christopher P., additional, Langenberg, Claudia, additional, and Codd, Veryan, additional

Published
2020
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17. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication

Author

Denchi, Eros Lazzerini, Celli, Giulia, and de Lange, Titia

Subjects
Chromosome replication -- Analysis, DNA damage -- Analysis, Liver cells -- Research, Telomeres -- Research, Biological sciences
Abstract

Mouse liver cells are highly resistant to extensive telomere dysfunction and the consequences of telomere dysfunction in noncycling cells are determined by using conditional deletion of the telomeric protein TRF2 in hepatocytes. The nondividing hepatocytes are found to maintain and regenerate liver function despite substantial loss of telomere integrity.

Published
2006

23. Mitotic Evolution of Plasmodium falciparum Shows a Stable Core Genome but Recombination in Antigen Families

Author

Bopp, Selina E. R., primary, Manary, Micah J., additional, Bright, A. Taylor, additional, Johnston, Geoffrey L., additional, Dharia, Neekesh V., additional, Luna, Fabio L., additional, McCormack, Susan, additional, Plouffe, David, additional, McNamara, Case W., additional, Walker, John R., additional, Fidock, David A., additional, Denchi, Eros Lazzerini, additional, and Winzeler, Elizabeth A., additional

Published
2013
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37. Apaf-1 is a transcriptional target for E2F and p53

Author

Moroni, M. Cristina, primary, Hickman, Emma S., additional, Denchi, Eros Lazzerini, additional, Caprara, Greta, additional, Colli, Elena, additional, Cecconi, Francesco, additional, Müller, Heiko, additional, and Helin, Kristian, additional

Published
2001
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39. Nucleophosmin Is Required for DNA Integrity and p19Arf Protein Stability.

Author

Colombo, Emanuela, Bonetti, Paola, Denchi, Eros Lazzerini, Martinelli, Paola, Zamponi, Raffaella, Marine, Jean-Christophe, Helin, Kristian, Falini, Brunangelo, and Pelicci, Pier Giuseppe

Subjects
PHOSPHOPROTEINS, P53 protein, RIBOSE, CELL proliferation, DNA, TUMOR suppressor proteins, PROTEINS
Abstract

Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19Arf and is thought to be indispensable for ribogenesis, cell proliferation, and survival after DNA damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knockout strain. Lack of NPM expression results in accumulation of DNA damage, activation of p53, widespread apoptosis, and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and rapidly acquire a senescent phenotype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Aft, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM. [ABSTRACT FROM AUTHOR]

Published
2005
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40. Mitotic Evolution of Plasmodium falciparum Shows a Stable Core Genome but Recombination in Antigen Families

Author

Bopp, Selina E. R., Manary, Micah J., Bright, A. Taylor, Chi-Johnston, Geoffrey Louis, Dharia, Neekesh V., Luna, Fabio L., McCormack, Susan, Plouffe, David, McNamara, Case W., Walker, John R., Fidock, David Armand, Denchi, Eros Lazzerini, and Winzeler, Elizabeth A.

Subjects
Plasmodium, FOS: Biological sciences, FOS: Clinical medicine, Immunology, Genetics, Microbiology, 3. Good health
Abstract

Malaria parasites elude eradication attempts both within the human host and across nations. At the individual level, parasites evade the host immune responses through antigenic variation. At the global level, parasites escape drug pressure through single nucleotide variants and gene copy amplification events conferring drug resistance. Despite their importance to global health, the rates at which these genomic alterations emerge have not been determined. We studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure. A combination of whole-genome microarray analysis and next-generation deep resequencing (totaling 14 terabases) revealed a stable core genome with only 38 novel single nucleotide variants appearing in seventeen evolved clones (avg. 5.4 per clone). In clones exposed to atovaquone, we found cytochrome b mutations as well as an amplification event encompassing the P. falciparum multidrug resistance associated protein (mrp1) on chromosome 1. We observed 18 large-scale (greater than 1 kb on average) deletions of telomere-proximal regions encoding multigene families, involved in immune evasion (9.5×10−6 structural variants per base pair per generation). Six of these deletions were associated with chromosomal crossovers generated during mitosis. We found only minor differences in rates between genetically distinct strains and between parasites cultured in the presence or absence of drug. Using these derived mutation rates for P. falciparum (1.0–9.7×10−9 mutations per base pair per generation), we can now model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions. Further, the detection of mitotic recombination events in var gene families illustrates how multigene families can arise and change over time in P. falciparum. These results will help improve our understanding of how P. falciparum evolves to evade control efforts within both the individual hosts and large populations.

41. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, Chen, Stoma, Svetlana, Lotta, Luca A, Warner, Sophie, Albrecht, Eva, Allione, Alessandra, Arp, Pascal P, Broer, Linda, Buxton, Jessica L, Da Silva Couto Alves, Alexessander, Deelen, Joris, Fedko, Iryna O, Gordon, Scott D, Jiang, Tao, Karlsson, Robert, Kerrison, Nicola, Loe, Taylor K, Mangino, Massimo, Milaneschi, Yuri, Miraglio, Benjamin, Pervjakova, Natalia, Russo, Alessia, Surakka, Ida, Van Der Spek, Ashley, Verhoeven, Josine E, Amin, Najaf, Beekman, Marian, Blakemore, Alexandra I, Canzian, Federico, Hamby, Stephen E, Hottenga, Jouke-Jan, Jones, Peter D, Jousilahti, Pekka, Mägi, Reedik, Medland, Sarah E, Montgomery, Grant W, Nyholt, Dale R, Perola, Markus, Pietiläinen, Kirsi H, Salomaa, Veikko, Sillanpää, Elina, Suchiman, H Eka, Van Heemst, Diana, Willemsen, Gonneke, Agudo, Antonio, Boeing, Heiner, Boomsma, Dorret I, Chirlaque, Maria-Dolores, Fagherazzi, Guy, Ferrari, Pietro, Franks, Paul, Gieger, Christian, Eriksson, Johan Gunnar, Gunter, Marc, Hägg, Sara, Hovatta, Iiris, Imaz, Liher, Kaprio, Jaakko, Kaaks, Rudolf, Key, Timothy, Krogh, Vittorio, Martin, Nicholas G, Melander, Olle, Metspalu, Andres, Moreno, Concha, Onland-Moret, N Charlotte, Nilsson, Peter, Ong, Ken K, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Pedersen, Nancy L, Penninx, Brenda WJH, Quirós, J Ramón, Jarvelin, Marjo Riitta, Rodríguez-Barranco, Miguel, Scott, Robert A, Severi, Gianluca, Slagboom, P Eline, Spector, Tim D, Tjonneland, Anne, Trichopoulou, Antonia, Tumino, Rosario, Uitterlinden, André G, Van Der Schouw, Yvonne T, Van Duijn, Cornelia M, Weiderpass, Elisabete, Denchi, Eros Lazzerini, Matullo, Giuseppe, Butterworth, Adam S, Danesh, John, Samani, Nilesh J, Wareham, Nicholas J, Nelson, Christopher P, Langenberg, Claudia, and Codd, Veryan

Subjects
age-related disease, Nucleotides, biological aging, telomere length, Leukocytes, Humans, Telomere, Mendelian randomisation, 3. Good health, Genome-Wide Association Study
Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

42. DUB-resistant ubiquitin to survey ubiquitination switches in mammalian cells.

Author

Békés M, Okamoto K, Crist SB, Jones MJ, Chapman JR, Brasher BB, Melandri FD, Ueberheide BM, Denchi EL, and Huang TT

Subjects
Amino Acid Sequence, Cell Line, Tumor, DNA Damage, HEK293 Cells, Humans, Molecular Sequence Data, Proliferating Cell Nuclear Antigen metabolism, Ubiquitin genetics, Ubiquitin-Specific Proteases metabolism, Ubiquitination, Ubiquitin metabolism
Abstract

The ubiquitin-modification status of proteins in cells is highly dynamic and maintained by specific ligation machineries (E3 ligases) that tag proteins with ubiquitin or by deubiquitinating enzymes (DUBs) that remove the ubiquitin tag. The development of tools that offset this balance is critical in characterizing signaling pathways that utilize such ubiquitination switches. Herein, we generated a DUB-resistant ubiquitin mutant that is recalcitrant to cleavage by various families of DUBs both in vitro and in mammalian cells. As a proof-of-principle experiment, ectopic expression of the uncleavable ubiquitin stabilized monoubiquitinated PCNA in the absence of DNA damage and also revealed a defect in the clearance of the DNA damage response at unprotected telomeres. Importantly, a proteomic survey using the uncleavable ubiquitin identified ubiquitinated substrates, validating the DUB-resistant ubiquitin expression system as a valuable tool for interrogating cell signaling pathways., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2013
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