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1.
PLoS Genet ; 12(7): e1006144, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27386863

RESUMO

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan.


Assuntos
Aterosclerose/genética , Neoplasias/genética , Homeostase do Telômero/genética , Telômero/genética , Envelhecimento/genética , Aterosclerose/patologia , Humanos , Longevidade/genética , Neoplasias/patologia , Encurtamento do Telômero
2.
Hum Mol Genet ; 25(11): 2324-2330, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26936823

RESUMO

Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.


Assuntos
Leucócitos/citologia , Homeostase do Telômero/genética , Encurtamento do Telômero/genética , Telômero/genética , Adolescente , Adulto , Negro ou Afro-Americano/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , População Negra/genética , Criança , Feminino , Deriva Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , População Branca/genética
3.
Nucleic Acids Res ; 44(10): 4871-80, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27131364

RESUMO

The Fanconi anemia protein SLX4 assembles a genome and telomere maintenance toolkit, consisting of the nucleases SLX1, MUS81 and XPF. Although it is known that SLX4 acts as a scaffold for building this complex, the molecular basis underlying this function of SLX4 remains unclear. Here, we report that functioning of SLX4 is dependent on its dimerization via an oligomerization motif called the BTB domain. We solved the crystal structure of the SLX4BTB dimer, identifying key contacts (F681 and F708) that mediate dimerization. Disruption of BTB dimerization abrogates nuclear foci formation and telomeric localization of not only SLX4 but also of its associated nucleases. Furthermore, dimerization-deficient SLX4 mutants cause defective cellular response to DNA interstrand crosslinking agent and telomere maintenance, underscoring the contribution of BTB domain-mediated dimerization of SLX4 in genome and telomere maintenance.


Assuntos
Endonucleases/metabolismo , Recombinases/química , Linhagem Celular , Interações Hidrofóbicas e Hidrofílicas , Mitomicina/toxicidade , Domínios Proteicos , Multimerização Proteica , Recombinases/metabolismo , Telômero/enzimologia , Telômero/ultraestrutura
4.
Nucleic Acids Res ; 43(12): 5912-23, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-25990736

RESUMO

SLX4 assembles a toolkit of endonucleases SLX1, MUS81 and XPF, which is recruited to telomeres via direct interaction of SLX4 with TRF2. Telomeres present an inherent obstacle for DNA replication and repair due to their high propensity to form branched DNA intermediates. Here we provide novel insight into the mechanism and regulation of the SLX4 complex in telomere preservation. SLX4 associates with telomeres throughout the cell cycle, peaking in late S phase and under genotoxic stress. Disruption of SLX4's interaction with TRF2 or SLX1 and SLX1's nuclease activity independently causes telomere fragility, suggesting a requirement of the SLX4 complex for nucleolytic resolution of branched intermediates during telomere replication. Indeed, the SLX1-SLX4 complex processes a variety of telomeric joint molecules in vitro. The nucleolytic activity of SLX1-SLX4 is negatively regulated by telomeric DNA-binding proteins TRF1 and TRF2 and is suppressed by the RecQ helicase BLM in vitro. In vivo, in the presence of functional BLM, telomeric circle formation and telomere sister chromatid exchange, both arising out of nucleolytic processing of telomeric homologous recombination intermediates, are suppressed. We propose that the SLX4-toolkit is a telomere accessory complex that, in conjunction with other telomere maintenance proteins, ensures unhindered, but regulated telomere maintenance.


Assuntos
Recombinases/metabolismo , Telômero/metabolismo , Ciclo Celular , DNA/metabolismo , Endodesoxirribonucleases , Endonucleases/metabolismo , Células HeLa , Recombinação Homóloga , Humanos , RecQ Helicases/metabolismo , Troca de Cromátide Irmã , Proteínas de Ligação a Telômeros/metabolismo
5.
J Med Genet ; 52(3): 157-62, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25624462

RESUMO

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24). CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.


Assuntos
Proteínas de Transporte/genética , Leucócitos/citologia , Melanoma/genética , Homeostase do Telômero/genética , Alelos , Proteínas de Transporte/biossíntese , Proteínas de Transporte/sangue , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Melanoma/sangue , Melanoma/patologia , Fatores de Risco , Telômero/genética
6.
Nucleic Acids Res ; 42(9): 5671-88, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24623817

RESUMO

A variety of human tumors employ alternative and recombination-mediated lengthening for telomere maintenance (ALT). Human RecQ helicases, such as BLM and WRN, can efficiently unwind alternate/secondary structures during telomere replication and/or recombination. Here, we report a novel role for RECQL1, the most abundant human RecQ helicase but functionally least studied, in telomere maintenance. RECQL1 associates with telomeres in ALT cells and actively resolves telomeric D-loops and Holliday junction substrates. RECQL1 physically and functionally interacts with telomere repeat-binding factor 2 that in turn regulates its helicase activity on telomeric substrates. The telomeric single-stranded binding protein, protection of telomeres 1 efficiently stimulates RECQL1 on telomeric substrates containing thymine glycol, a replicative blocking lesion. Loss of RECQL1 results in dysfunctional telomeres, telomere loss and telomere shortening, elevation of telomere sister-chromatid exchanges and increased aphidicolin-induced telomere fragility, indicating a role for RECQL1 in telomere maintenance. Further, our results indicate that RECQL1 may participate in the same pathway as WRN, probably in telomere replication.


Assuntos
RecQ Helicases/fisiologia , Homeostase do Telômero , Animais , Replicação do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Exodesoxirribonucleases/metabolismo , Células HeLa , Humanos , Ligação Proteica , Transporte Proteico , RecQ Helicases/metabolismo , Telomerase/metabolismo , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Helicase da Síndrome de Werner
8.
Aging Cell ; 14(4): 701-3, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25865872

RESUMO

Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an 'epigenetic' mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age-dependent germ stem cell selection process, whereby the selected stem cells have longer telomeres, are more homogenous with respect to telomere length, and share resistance to aging.


Assuntos
Envelhecimento/genética , Células Germinativas/metabolismo , Idade Paterna , Telômero/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Epigênese Genética , Feminino , Expressão Gênica , Células Germinativas/citologia , Humanos , Padrões de Herança , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Células-Tronco/citologia , Células-Tronco/metabolismo , Telomerase/genética , Telômero/química , Homeostase do Telômero , Encurtamento do Telômero
9.
Int J Epidemiol ; 43(6): 1799-805, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25056338

RESUMO

BACKGROUND: In eutherian mammals and in humans, the female fetus may be masculinized while sharing the intra-uterine environment with a male fetus. Telomere length (TL), as expressed in leukocytes, is heritable and is longer in women than in men. The main determinant of leukocyte TL (LTL) is LTL at birth. However, LTL is modified by age-dependent attrition. METHODS: We studied LTL dynamics (LTL and its attrition) in adult same-sex (monozygotic, n = 268; dizygotic, n = 308) twins and opposite-sex (n = 144) twins. LTL was measured by Southern blots of the terminal restriction fragments. RESULTS: We observed that in same-sex (both monozygotic and dizygotic) twins, as reported in singletons, LTL was longer in females than in males [estimate ± standard error (SE):163 ± 63 bp, P < 0.01]. However, in opposite-sex twins, female LTL was indistinguishable from that of males (-31 ± 52 bp, P = 0.6), whereas male LTL was not affected. Findings were similar when the comparison was restricted to opposite-sex and same-sex dizygotic twins (females relative to males: same-sex: 188 ± 90 bp, P < 0.05; other-sex: -32 ± 64 bp, P = 0.6). CONCLUSIONS: These findings are compatible with masculinization of the female fetus in opposite-sex twins. They suggest that the sex difference in LTL, seen in the general population, is largely determined in utero, perhaps by the intrauterine hormonal environment. Further studies in newborn twins are warranted to test this thesis.


Assuntos
Envelhecimento/genética , Telômero/metabolismo , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto , Southern Blotting , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
10.
Cell Rep ; 4(5): 861-9, 2013 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-24012755

RESUMO

SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance.


Assuntos
Reparo do DNA , Endonucleases/metabolismo , Recombinases/metabolismo , Telômero/metabolismo , Endonucleases/genética , Humanos , Recombinases/genética , Telômero/genética
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