Structural Chromosomal Aberrations

Translocations, Chromosomal Breaks, and Fragile Sites Chromosomal translocations are structural aberrations characterized by relocations of chromosomal segments within one or among different chromosomes. As chromosomal translocations are relatively stable structural changes (76-78), they would be expected to accumulate with age. Several investigators have found that the increase in translocation frequencies in a nonsmoking normal population follows a curvilinear relationship with age...

Introduction

Dyskeratosis congenita (DKC), or Zinsser-Engman-Cole syndrome, is a congenital, multisystem disorder first described by Zinsser in 1906, followed by Engman in 1926, and Cole in 1930. DKC was originally described as a rare skin disease characterized in the early stages by reticulate skin pigmentation, nail dystrophy, and leukoplakias of the tongue. With an accumulation of clinical reports, it is now apparent that DKC is a bone marrow failure syndrome. This syndrome initially manifests as severe...

Association of Nibrin with BRCA1

Another participant in the functional cellular response to IR seems to be BRCA1. Zhong et al (125) have demonstrated that BRCA1 is associated with the M R N complex based on its temporal and spatial colocalization in IRIF. The formation of IRIF is dramatically reduced in breast cancer cells carrying a homozygous BRCA1 mutation, whereas ectopic expression of wild-type, but not mutated, BRCA1 restores IRIF formation. Restoration of IRIF formation by wild-type BRCA1 renders the cells less...

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Figure 4 Decreased viability of late-generation Terc ' mice. Late-generation Terc ' mice in a pure C57BL6 background show decreased viability with age. Fifty percent of the G4 Terc ' mice died at 5 months of age. C57BL 6 background, which shows shorter, more homogeneous telomeres, 50 of late-generation Tercw mice died at 5 months of age (45) (Fig. 4). Death of these mice occurred within 48 hr of the detection of symptoms of poor health, such as reduced activity, lowered responsiveness to...

Molecular Analyses Of Nibrin Function

Nibrin Is Associated in a Tumeric Complex with hMre11 and hRad50 Similar to the situation in yeast, the hMrell and hRad50 proteins are found tightly associated in human cells, presumably interacting directly and independently of nibrin 65,66,116 . hRad50, a coiled-coil structural maintenance of chromosomes SMC protein, has ATP-dependent DNA-binding activity 117 . hMrell is expected to have structural DNA-binding activities as well as catalytic activities including single-stranded...

Chromatin Perturbations

Agents that decondense or open chromatin structure, such as histone deacetylase inhibitors 21 or thymidine analogues 71 , can cause cells to arrest growth with a senescent phenotype. The senescence arrest generally occurs within a few cell cycles, and is irreversible even after the agents are withdrawn. Chromatin structure has long been thought to play a role in telomere-dependent and telomere-independent senescence 72,73 . In the case of telomere-dependent senescence, the telomere is thought...

Chromosomal Analysis In Progeria

Mosaic Chromosome Disorder

Of more than 20 cases of progeria of which we are aware that have been analyzed for chromosomal abnormalities 1-3 , none has been found to be abnormal with one exception. This was an identical twin with progeria 3 . He died of heart disease at the age of 8 years and 1 month following the death of his twin brother. Both twins had a severely affected phenotype, with hypoplastic leg and arm development, although both were of normal intelligence. A postmortem skin biopsy was obtained and cultured....

Phenotype Of Atm Knockout Mice

Several different strains of Atm ' mice have been generated since the cloning of the ATM gene 96,99,148 . The mice all have a similar AT-like phenotypes in that they express neurological abnormalities, immune defects, genetic instability, radiation sensitivity, infertility, and a high incidence of lymphoma. Despite these phenotypic similarities with AT patients, there are differences, including severe growth retardation, universal sterility, and death from lymphoma by age 6 months in Atm ' mice...

Hyaluronic Acid Urinary Levels In Progeria

Progeria Life Cycle

A potential marker for both progeria and WS appears to be urinary HA excretion. HA excretion has been found to be elevated in these two syndromes and has not been reported to be elevated for any other genetic disease. HA levels in controls are normally considered to represent less than 1 of total glycosaminoglycans GAGs . Elevated HA levels have been reported to vary from 2 to 22 of total GAGs in a series of Japanese WS subjects 65 . Urinary HA, as a percentage of total GAGs present, also was...

References

Cancer, aging and cellular senescence. In Vivo 14 183-188, 2000. 2. L Balducci, C Beghe. Cancer and age in USA. CritRev Oncol Hematol 37 137-145, 2001. 3. RA DePinho. The age of cancer. Nature 408 248-254, 2000. 4. JM Bishop. Cancer the rise of the genetic paradigm. Genes Dev 9 1309-1315, 1995. 5. DP Cahill, KW Kinzler, B Vogelstein, C Lengauer. Genetic instability and Darwinian selection in tumours. Trends Cell Biol 9 57-60, 1999. 6. MJ Arends, AH Wyllie. Apoptosis mechanisms and...

Mitochondria Aging and Human Disease

Age-related declines in activities of enzymes of oxidative phosphorylation, a critical mitochondrial process that produces energy in the form of adenosine triphos-phate, have been shown in several tissues including brain and skeletal muscle. Mutations accumulate in mitochondrial DNA with age in somatic tissues 39 . In one study, a common 5-kb deletion has been shown to increase 10,000-fold from young to old individuals, with regional differences between the basal ganglia, cerebellum, and cortex...

Paternal Age Effect In Progeria

Figure 2 Paternal age effect noted in progeria. Ages of fathers and mothers of 24 cases of progeria are compared with control fathers' ages. Approximately 20 of the fathers were about 20 years older than the mothers. pected to be 25 . In progeria, it is clearly much less than 25 . Almost all cases are sporadic, and there is no evidence of increased miscarriage rates to suggest selection against the homozygote in utero. A case of identical twins with progeria with 14 normal siblings has been...

Biochemical Features Of The Recq4 Helicase

Structural Similarities to Other RecQ Helicase Family Members The RECQL4 helicase has a helicase domain that contains seven consensus motifs in the middle of the molecule see Fig. 2 . The amino acid sequence of the helicase domain is 40.8 homologous to that of the E. coli RecQ helicase, the prototype of this family, within the same range as the other four family members, RECQL, WRN, BLM, and RECQ5 helicases. Of the five human RecQ helicases, defective WRN, BLM, and RECQL4 helicases are...

Atm Gene

Atm Mutations

An intensive search for the genes responsible for AT culminated in 1995 with the positional cloning of the ATM gene by Shiloh and colleagues 116 . The ATM gene is conserved in vertebrates and codes for a 12 kb transcript that is abundantly expressed in multiple tissues in vivo. The carboxy terminus of the ATM protein shares homology with several other checkpoint damage response proteins, including Schizosaccharomyces pombe Rad3p, Saccharomyces cerevisiae Mec1p, Saccharomyces cerevisiae Tel1p,...