Disease relevance of Genomic Instability

• Fanconi anaemia (FA) is an autosomal-recessive disorder characterized by genomic instability, developmental defects, DNA crosslinking agent hypersensitivity and cancer susceptibility [1].
• Moreover, H2AX haploinsufficiency caused genomic instability in normal cells and, on a p53-deficient background, early onset of various tumors including more mature B lymphomas [2].
• These include the FKBP12-rapamycin-binding proteins Tor1p, Tor2p, and FRAP, S. pombe rad3, and the product of the ataxia telangiectasia gene, mutations in which lead to genomic instability and predisposition to cancer [3].
• Ataxia-telangiectasia (A-T) results from the loss of ataxia-telangiectasia mutated (Atm) function and is characterized by accelerated telomere loss, genomic instability, progressive neurological degeneration, premature ageing and increased neoplasia incidence [4].
• PURPOSE: We evaluated the relationship between p53 mutation and the major form of genomic instability in sporadic colorectal tumors, namely, that involving DNA breakage, which leads to chromosomal translocations, insertions, deletions, and gene amplification [5].

High impact information on Genomic Instability

• The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast [6].
• We review Sir2, a factor linking genomic stability, metabolism, and aging [7].
• Here we provide evidence that a prototypical SR protein, ASF/SF2, is unexpectedly required for maintenance of genomic stability [8].
• Research on the Werner syndrome and a surprising number of other progeroid syndromes support the importance of the maintenance of genomic stability as a partial antidote to aging [9].
• These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging [10].

Chemical compound and disease context of Genomic Instability

• This preferential enhancement of genomic instability in malignant 10T1/2 mouse cells suggests that 17beta-estradiol may accelerate the accumulation of mutations, and therefore may represent a mechanism by which the female hormone contributes to breast cancer development [11].
• We tested the hypothesis that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, folic acid deficiency and riboflavin deficiency, independently or interactively, are important determinants of genomic stability, cell death, cell proliferation and homocysteine (Hcy) concentration in 9-d human lymphocyte cultures [12].
• One rare and interesting finding was noted in a single mouse treated with UTH, where a mammary metastasis had an MF approximately 10-fold greater than the parent tumor, with 75% of the mutations independent, providing strong evidence of genomic instability [13].
• Serum AFP concentration, HBV infection, tumor size, histological grade, tumor capsule invasion, as well as intrahepatic metastasis were associated with the genomic instability on certain primers [14].
• Although the exact mechanisms by which this vitamin deficiency may cause these diseases are not known at the present time, recent work has shown that folate deficiency also causes genomic instability and programmed cell death (or apoptosis) [15].

Biological context of Genomic Instability

• Mismatch repair has a central role in maintaining genomic stability by repairing DNA replication errors and inhibiting recombination between non-identical (homeologous) sequences [16].
• At the checkpoint between the prereplicative phase of growth and the phase of chromosome replication, cells lacking p21 failed to arrest the cell cycle in response to DNA damage, but their apoptotic response and genomic stability were unaltered [17].
• PARP is important for genomic stability but dispensable in apoptosis [18].
• Mammary tumors lacking p53 display less fibrotic histopathology and increased genomic instability with aneuploidy, amplifications, and deletions, as detected by karyotype analysis and comparative genomic hybridization [19].
• The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1) [20].

Anatomical context of Genomic Instability

• Alterations in the expression and activity of the centrosomal kinase, Aurora-A/serine/threonine kinase 15 (STK15), affect genomic stability, disrupt the fidelity of centrosome duplication, and induce cellular transformation [21].
• Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1 [22].
• In the present study, we have used hTERT to extend the life span of normal human skin fibroblasts derived from patients afflicted with syndromes of genomic instability and/or premature aging [23].
• The effects of c-Myc overexpression were studied in human mammary epithelial cells (HMEC) as one approach to understanding the c-Myc-induced genomic instability in the context of mammary tumorigenesis [24].
• We propose how the combined actions of the RAG1 domains may function in V(D)J recombination and also in aberrant cleavage reactions that may lead to genomic instability in B and T lymphocytes [25].

Associations of Genomic Instability with chemical compounds

• BLM is thought to participate in several DNA transactions, the failure of which could give raise to genomic instability, and to interact with many proteins involved in replication, recombination, and repair [26].
• Moreover, BubR1(+/-)Apc(Min)(/+) MEFs slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than that of WT or BubR1(+/-) or Apc(Min)(/+) MEFs, accompanied by premature separation of sister chromatids [27].
• Treatment of PARP-/- mice either by the alkylating agent N-methyl-N-nitrosourea (MNU) or by gamma-irradiation revealed an extreme sensitivity and a high genomic instability to both agents [28].
• The data presented indicate that estrogen-induced genomic instability may be a key element in carcinogenic processes induced by estrogens [29].
• These results add to the accumulating clinical and experimental evidence relating chronic folate deficiency to genomic instability and carcinogenesis [30].

Gene context of Genomic Instability

• Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair [31].
• Genomic instability in Gadd45a-deficient mice [32].
• In the yeast Saccharomyces cerevisiae, the absence of the Sgs1 helicase results in genomic instability and accelerated ageing [33].
• MYC overexpression exacerbates genomic instability and sensitizes cells to apoptotic stimuli [34].
• The yeast checkpoint kinases Mec1 and Rad53 are required for genomic stability in the presence of replicative stress [35].

Analytical, diagnostic and therapeutic context of Genomic Instability

• In order to determine whether such proteins specifically influence genomic instability, mice deficient for Hsp70.1 and Hsp70.3 (Hsp70.1/3(-/-) mice) were generated by gene targeting [36].
• In this first study of human ACF with this approach, the finding of altered DNA fingerprints in these microscopic lesions suggests that genomic instability can occur very early in human colon tumorigenesis [37].
• The initial molecular dissection of BCR-ABL has linked the expression of this constitutively activated kinase with enhanced genomic instability [38].
• Chromosomal instability, measured by both karyotypic and FISH (fluorescence in situ hybridization) analyses, was reduced but not abrogated by hTERT transduction, suggesting that telomerase expression can enhance genomic stability [39].
• Cytokinesis-block micronucleus (CB-MN) assay and single-cell gel electrophoresis (SCGE) were employed to analyze leukocytes from 14 Fanconi anemia (FA) patients, 30 Down syndrome (DS) patients, and 30 control individuals, to examine the sensitivity of these techniques to detect genomic instability in these 2 diseases [40].

References