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Telomeres and epigenetics. The structure of mammalian telomeres Telomeres contain a double-stranded DNA region of TTAGGG repeats (green arrows) Telomeres.

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Presentation on theme: "Telomeres and epigenetics. The structure of mammalian telomeres Telomeres contain a double-stranded DNA region of TTAGGG repeats (green arrows) Telomeres."— Presentation transcript:

1 Telomeres and epigenetics

2 The structure of mammalian telomeres Telomeres contain a double-stranded DNA region of TTAGGG repeats (green arrows) Telomeres contain a double-stranded DNA region of TTAGGG repeats (green arrows) Telomeres are characterized by a 150–200-nt long single- stranded overhang of the G-rich strand (G-strand overhang; blue arrows) Telomeres are characterized by a 150–200-nt long single- stranded overhang of the G-rich strand (G-strand overhang; blue arrows) Telomerase recognizes the 3' OH at the end of the G-strand overhang, leading to telomere elongation. Telomerase recognizes the 3' OH at the end of the G-strand overhang, leading to telomere elongation.

3 Telomerase enzyme (Cc) Ribonuleoprotein Ribonuleoprotein TERT, telomerase reverse transcriptase TERT, telomerase reverse transcriptase TERC, telomerase RNA component (single RNA molecule provides an AAUCCC (in mammals) template to guide the insertion of TTAGGG TERC, telomerase RNA component (single RNA molecule provides an AAUCCC (in mammals) template to guide the insertion of TTAGGG DKC1, dyskeratosis congenita 1 DKC1, dyskeratosis congenita 1

4 Components of telomeric proteins Two main protein complexes are bound to telomeres, the telomere repeat binding factor 1 and 2 complexes, TRF1 and TRF2 Two main protein complexes are bound to telomeres, the telomere repeat binding factor 1 and 2 complexes, TRF1 and TRF2 The components of the telomere repeat binding factor 1 (TRF1) (Ca) and 2 (TRF2) (Cb) complexes and are shown. The components of the telomere repeat binding factor 1 (TRF1) (Ca) and 2 (TRF2) (Cb) complexes and are shown. human diseases in which expression of these components has been shown to be altered are indicated human diseases in which expression of these components has been shown to be altered are indicated

5 A telomere in a T-loop conformation Strand invasion of the G- strand overhang is highlighted in red This conformation might prevent the access of telomerase to the 3' OH at the chromosome end.

6 Telomerase and telomere length in ageing Telomerase and telomere length in ageing Most somatic cells show progressive telomere shortening owing to low or absent telomerase activity Most somatic cells show progressive telomere shortening owing to low or absent telomerase activity leads to critically short telomeres, which triggers a DNA damage response that results in chromosomal end-to-end fusions or cell arrest and apoptosis. leads to critically short telomeres, which triggers a DNA damage response that results in chromosomal end-to-end fusions or cell arrest and apoptosis. thought to contribute to the onset of degenerative diseases including human premature ageing syndromes thought to contribute to the onset of degenerative diseases including human premature ageing syndromes

7 Telomerase and telomere length in tumourigenesis Tumour cells have shorter telomeres than normal cells However, telomerase is reactivated in more than 90% of all types of human tumours therapeutic strategies aimed at inhibiting telomerase will preferentially kill tumour cells and have no toxicity on normal cells.

8 Premature ageing syndromes with short telomeres Ataxia telangiectasia (ATM) Werner syndrome (WRN); Bloom syndrome (BLM); Dyskeratosis congenita (DKC1, Terc); aplastic anaemia (Terc, Tert); Fanconi anaemia (FANC genes); Nijmegen breakage syndrome (NBS); and ataxia telangiectasia-like disorder (MRE11).

9 Ataxia Telangiectasia A-T is fatal in the second or third decade of life Staggering gait, muscular unco-ordination Staggering gait, muscular unco-ordination Immunodeficiency Immunodeficiency Neurodegeneration Neurodegeneration premature aging premature aging Skin sensitivity to ionizing radiation Skin sensitivity to ionizing radiation susceptibility to certain types of cancer (breast cancer) susceptibility to certain types of cancer (breast cancer)

10 Ataxia Telangiectasia Mutations in ATM gene located on chromosome 11q22-q23 encodes large protein kinase involved in cell cycle checkpoint and genotoxic stress responses Homozygous ATM mutant alleles rare ~ 1/40,000 heterozygous carriers ~ 1-2% Carriers exhibit intermediate sensitivity to radiation and predisposition to cancer (implications for radiotherapy)

11 Werner syndrome (WRN short stature (common from childhood on) wrinkled skin baldness, cataracts, muscular atrophy tendency to diabetes mellitus gene WRN mapped to chromosome 8 predicted helicase belonging to the RecQ family

12 FANCONI/BRCA1/BRCA2/ATM/NBS1 PATHWAY

13 Epigenetics epigenetic modification of DNA in mammals is methylation of cytosine at position C5 in CpG dinucleotides Other main group is epigenetic post- translational modification of histones

14 Genomic imprinting defined as an epigenetic modification of a specific parental chromosome in the gamete or zygote that leads to differential expression of the two alleles of a gene in the somatic cells of the offspring. Differential expression can occur in all cells, or in specific tissues or developmental stages. About 80 genes are known to be imprinted Loss of imprinting (LOI) disruption of imprinted epigenetic marks through gain or loss of DNA methylation, or simply the loss of normal allele-specific gene expression.

15 Epigenetics – differential imprinting failure to thrive during infancy, hyperphagia and obesity during early childhood, mental retardation, and behavioural problems molecular defect involves a paternally imprinted domain at 15q11–q13 Prader-Willi syndrome Angelman syndrome abnormal gait speech impairment, speech impairment, seizures, mental retardation inappropriate happy demeanor that includes frequent laughing, smiling, excitability defect lies within the maternally imprinted domain at 15q11–q13

16 Genetic causes 70% have a deletion of the PWS/AS region on their paternal chromosome 15 25% have maternal uniparental disomy for chromosome 15 (the individual inherited both chromosomes from the mother, and none from the father) 5% have an imprinting defect <1% have a chromosome abnormality including the PWS/AS region Prader-Willi syndromeAngelman syndrome 70% have a deletion of the PWS/AS region on their maternal chromosome 15 7% have paternal uniparental disomy for chromosome 15 (the individual inherited both chromosomes from the father, and none from the mother) 3% have an imprinting defect 11% have a mutation in UBE3A 1% have a chromosome rearrangement 11% have a unknown genetic cause

17 DNA methylation and cancer Changes in methylation are early events in tumorigenesis In tumour cells, repeat-rich heterochromatin becomes hypermethylated and this contributes to genomic instability, a hallmark of tumour cells, through increased mitotic recombination events. De novo hypomethylation of CpG islands also occurs in cancer cells, and can result in the transcriptional silencing of growth-regulatory genes. Region of the genome showing repeat-rich, hypermethylated pericentromeric heterochromatin and tumour suppressor gene (TSG) associated with a hypomethylated CpG island (red).

18 References 1) Telomeres and human disease by M Blasco Nature Reviews Genetics Aug 2005 vol 6 pp611 2) DNA methylation and human disease by KD Robertson Nature Reviews Genetics Aug 2005 vol 6 pp 597 Nature Reviews Genetics Aug 2005 vol 6 pp 597


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