Transcript powerpoint

Telomeres and epigenetics
The structure of mammalian telomeres
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Telomeres contain a double-stranded DNA region of TTAGGG
repeats (green arrows)
Telomeres are characterized by a 150–200-nt long singlestranded 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 enzyme (Cc)
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Ribonuleoprotein
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TERT, telomerase reverse
transcriptase
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TERC, telomerase RNA
component (single RNA
molecule provides an
AAUCCC (in mammals)
template to guide the
insertion of TTAGGG
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DKC1, dyskeratosis
congenita 1
Components of telomeric proteins
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Two main protein complexes
are bound to telomeres, the
telomere repeat binding
factor 1 and 2 complexes,
TRF1 and TRF2
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The components of the
telomere repeat binding
factor 1 (TRF1) (Ca) and 2
(TRF2) (Cb) complexes and
are shown.
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human diseases in which
expression of these
components has been shown
to be altered are indicated
A telomere in a T-loop conformation
Strand invasion of the Gstrand overhang is
highlighted in red
This conformation might
prevent the access of
telomerase to the 3' OH at
the chromosome end.
Telomerase and telomere length in
ageing
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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.
thought to contribute to
the onset of degenerative
diseases including human
premature ageing
syndromes
Telomerase and telomere length in
tumourigenesis
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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.
Premature ageing syndromes with
short telomeres
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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).
Ataxia Telangiectasia
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Staggering gait, muscular unco-ordination
Immunodeficiency
Neurodegeneration
premature aging
Skin sensitivity to ionizing radiation
susceptibility to certain types of cancer
(breast cancer)
A-T is fatal in the second or third decade of life
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)
Werner syndrome (WRN
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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
FANCONI/BRCA1/BRCA2/ATM/NBS1 PATHWAY
Epigenetics
epigenetic modification of
DNA in mammals is
methylation of cytosine
at position C5 in CpG
dinucleotides
Other main group is
epigenetic posttranslational
modification of histones
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)
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disruption of imprinted epigenetic marks through gain or loss of
DNA methylation, or simply the loss of normal allele-specific
gene expression.
Epigenetics – differential imprinting
Prader-Willi syndrome
Angelman syndrome
failure to thrive during infancy,
hyperphagia and obesity during
early childhood, mental
retardation, and behavioural
problems
abnormal gait
speech impairment,
seizures, mental retardation
inappropriate happy demeanor that
includes frequent laughing,
molecular defect involves a
paternally imprinted domain at
15q11–q13
smiling, excitability
defect lies within the maternally
imprinted domain at 15q11–q13
Genetic causes
Prader-Willi syndrome
Angelman syndrome
70% have a deletion of the
PWS/AS region on their
paternal chromosome 15
70% have a deletion of the PWS/AS
region on their maternal
chromosome 15
25% have maternal
uniparental disomy for
chromosome 15 (the
individual inherited both
chromosomes from the
mother, and none from the
father)
7% have paternal uniparental
disomy for chromosome 15 (the
individual inherited both
chromosomes from the father, and
none from the mother)
5% have an imprinting
defect
<1% have a chromosome
abnormality including the
PWS/AS region
3% have an imprinting defect
11% have a mutation in UBE3A
1% have a chromosome
rearrangement
11% have a unknown genetic cause
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).
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