The premature ageing syndromes: insights into the ageing process

Dyer, Christopher; Sinclair, Alan J.

doi:10.1093/ageing/27.1.73

Cited by 43 publications

(28 citation statements)

References 47 publications

(46 reference statements)

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“…: 323-442-3950; Fax: 323-442-1721; E-mail: comai@hsc.usc.edu. 1 The abbreviations used are: WS, Werner syndrome; WRN, Werner Syndrome protein; HR, homologous recombination; NHEJ, non-homologous end joining; DSB, double strand break; DTT, dithiothreitol; PAGE, polyacrylamide gel electrophoresis; HCV, hepatitis C virus.…”

Section: Methodsmentioning

confidence: 99%

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Functional Interaction between Ku and the Werner Syndrome Protein in DNA End Processing

Comai

2000

Journal of Biological Chemistry

200

170

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Werner syndrome (WS) is an autosomal recessive disease characterized by premature aging. The gene responsible for the syndrome was recently cloned and shown to encode a protein with strong homology to DNA/RNA helicases. In addition, the Werner syndrome protein (WRN) possesses an exonuclease activity. Based on the homology to helicases it has been proposed that WRN functions in some aspects of DNA replication, recombination, or repair. However, there is currently no evidence of a role of WRN in any of these processes; therefore, its biological function remains unknown. Using a biochemical approach, we have identified two polypeptides that bind to the WRN protein. Peptide sequence analysis indicates that the two proteins are identical to Ku70 and Ku80, a heterodimer involved in double strand DNA break repair by non-homologous DNA end joining. Protein-protein interaction studies reveal that WRN binds directly to Ku80 and that this interaction is mediated by the amino terminus of WRN. In addition, we show that the binding of Ku alters the specificity of the WRN exonuclease. These results suggest a potential involvement of WRN in the repair of double strand DNA breaks.Werner syndrome (WS) 1 is a recessive autosomal disorder leading to premature aging (1). Individuals with WS develop accelerated atherosclerosis, osteoporosis, and a higher incidence of several types of tumors (2-4). Somatic cells of WS patients display a shortened replicative life span and elevated rates of chromosome translocation, rearrangements, and deletions (5, 6). The gene defective in WS has been identified and encodes a protein that possesses both exonuclease and helicase activities (7-13). A nuclear localization signal has also been identified at its carboxyl-terminal end. All the WS mutations that have been identified result in a nonsense mutation or frameshift, leading to a predicted truncated protein. Thus, it is thought that the truncated protein fails to enter the nucleus and is subsequently degraded. Immunocytochemical studies have localized the Werner syndrome protein (WRN) in the nucleoli of actively growing human cells, whereas serum deprivation causes a relocalization to the nucleus (14,15). Despite all the available information, the cellular function of WRN remains unknown (16). To understand the molecular basis of WS, we searched for nuclear factors that associate with the WRN protein. Here we report that WRN interacts with the Ku70/80 heterodimer (Ku), a factor involved in the repair of DNA double strand breaks (DSBs) (17)(18)(19)(20). More importantly, our results show that the exonuclease activity of WRN on 3Ј-recessed DNA ends is strongly stimulated by Ku. Moreover, in the presence of Ku, WRN can efficiently process both bluntended DNA and the 3Ј-protruding strand of a partial duplex DNA. These results suggest that WRN, through direct physical interaction with the Ku70/80 heterodimer, may be involved in processing of DSBs, providing a link between DNA repair and aging. EXPERIMENTAL PROCEDURESProtein Binding Assay and Peptide ...

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Section: Methodsmentioning

confidence: 99%

“…Werner syndrome (WS) 1 is a recessive autosomal disorder leading to premature aging (1). Individuals with WS develop accelerated atherosclerosis, osteoporosis, and a higher incidence of several types of tumors (2)(3)(4).…”

mentioning

confidence: 99%

Functional Interaction between Ku and the Werner Syndrome Protein in DNA End Processing

Comai

2000

Journal of Biological Chemistry

200

170

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“…27 Many overlapping and sometimes conflicting theories of ageing exist and the emergence of a unified theory still seems unlikely. Experimental studies of senescence are difficult to design because of the variable effect of diseases and other extrinsic factors.…”

Section: Pathophysiology Of Ageingmentioning

confidence: 99%

Hutchinson-Guilford progeria syndrome

Sarkar

Shinton

2001

Postgraduate Medical Journal

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“…own syndrome (DS), also known as trisomy 21, is the most common genetic disorder of live-born infants and has been long considered a model of accelerated aging (1). Cardiac malformations and predisposition to Alzheimer disease are prominent features of this syndrome (2,3).…”

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confidence: 99%

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Giménez‐Barcons

Casteràs

Armengol

et al. 2014

The Journal of Immunology

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Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.

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The premature ageing syndromes: insights into the ageing process

Cited by 43 publications

References 47 publications

Functional Interaction between Ku and the Werner Syndrome Protein in DNA End Processing

Functional Interaction between Ku and the Werner Syndrome Protein in DNA End Processing

Hutchinson-Guilford progeria syndrome

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

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