Download 1. dia

Manifestation of Novel Social Challenges of the
European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University
of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Manifestation of Novel Social Challenges of the
European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University
of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Krisztián Kvell
Molecular and Clinical Basics of Gerontology – Lecture
22
AGING AND GENE
EXPRESSION –
ALTERATIONS OF THE
GENOME DUE TO AGING
Telomere sequence and
telomerase function
TÁMOP-4.1.2-08/1/A-2009-0011
Telomerase
RNA template A A U C C C A
DNA
T T A
Nucleotides
TÁMOP-4.1.2-08/1/A-2009-0011
Telomeres as biological
clocks
• Most favored clock, but cause or
marker?
• Sequence: TTAGGG hexanucleotide >
1000x
• Polymerase leaves gap with every
replication
• Oxidative stress accelerates
telomere loss rate
Factors influencing
telomere loss rate
TÁMOP-4.1.2-08/1/A-2009-0011
• Telomeres form terminal loops for
stability
• Role of TRF2 in telomere
stability
• Issue of telomere length
threshold
• Issue of telomere loss rate vs.
stress rate
TÁMOP-4.1.2-08/1/A-2009-0011
Changes in telomere length
Embyonic
stem cells
Adult
stem cells
Extending the length of a
telomere
Chromosome
Telomere
long
Telomere
short
Active
telomerase
Telomerase
inactive
or absent
Short end of New
DNA DNA
G G T T A G G G T T A G
C
C
T C C C A
A A U
T C
A A U
RNA template
T T A G G G
A A T C C C
Telomere is repetitive DNA sequence
DNA polymerase
Telomerase
TÁMOP-4.1.2-08/1/A-2009-0011
Slowing, reversing telomere
shortening
• Counteracting (oxidative) stress
conditions
• Telomerase activity increases
telomere length
• ALT: alternative telomere
lengthening
TÁMOP-4.1.2-08/1/A-2009-0011
Significance of telomere in
cancer
Telomerase reactivation
Telomere lenght
Telomere
crisis
Normal tissue
Hyperplasia
Carcinoma in situ Invasive cancer
Number of aberrations
Genome instability
Loss of telomere function Further evolution
TÁMOP-4.1.2-08/1/A-2009-0011
Further clocks ticking
• Soluble factors / cell nonautonomous spreading
• Pineal clock, role of melatonin
• Circadian clock mechanisms
• DNA methylation, acetylation, deacetylation
TÁMOP-4.1.2-08/1/A-2009-0011
Genomic instability in
progeria types
• Werner-syndrome
• Cockayne syndrome
• Hutchinson-Guilford progeria
• Xeroderma pigmentosum
TÁMOP-4.1.2-08/1/A-2009-0011
Werner syndrome
• Homozygous recessive (skin,
cataract, diabetes mellitus
osteoporosis)
• WRN protein (anti-recombinase,
helicase, removes recombination
and repair intermediates)
• Defective transcription (50%)
• Relation with p53 (attenuated
apoptosis)
TÁMOP-4.1.2-08/1/A-2009-0011
Cockayne syndrome
• Rare segmental progeria
(dwarfism, photosensitivity,
neurological degeneration etc.)
• Defect in transcription coupled
repair (TCR)
• Defective 8-oxodG excision (50%)
• Subtypes: CS-A, CS-B
TÁMOP-4.1.2-08/1/A-2009-0011
Hutchinson-Guilford progeria
syndrome
• Lamin A mutation (nuclear
envelope fragility)
• Primerily affects mesenchymal
tissues
• HGPS cells have decreased stress
resistence
• Rapid progeria, premature death
TÁMOP-4.1.2-08/1/A-2009-0011
DNA damage: causes, results
I
Reactive oxygen species
(ROS)
DNA
REPAIR
Replication errors
X rays
UV light
(limited
synthesis:
small
fragments)
Cell cycle
arrest
(Apoptosis)
Alkylating agents
Spontaneous reactions
Mutations
Cancer and
genetic
diseases
TÁMOP-4.1.2-08/1/A-2009-0011
Oxidative DNA damage
• > 10,000 DNA lesions / cell / day
• A variety of DNA damage types (> 50
types)
• 5 distinctive groups
- Oxidized purines
- Oxidized pyrimidines
- Abasic sites
- Single-strand breaks
- Double-strand breaks
TÁMOP-4.1.2-08/1/A-2009-0011
DNA damage: causes, results
II
Metabolism
Exogenus
DNA damage
Stochastic
Dampened
GH/IGF axis
Cellular responses
(apoptosis,
senescence)
Mutations, epi-mutations
Tissue atrophy,
lost regeneration
Altered regulatory circuits
Regulated
Improved survival
Tissue/organ functional
decline, degenerative or
hyperplastic disease
TÁMOP-4.1.2-08/1/A-2009-0011
Oxidative DNA damage repair
types I
• Base excision repair (BER) is
most important, subtypes: AP
endonuclease or lyase repair
• Removal of oxidized purines (two
types of lesions: 8-oxodG and
formamido-pyrimidines)
• Removal of oxidized pyrimidines
(strong block, strongly
cytotoxic)
TÁMOP-4.1.2-08/1/A-2009-0011
Oxidative DNA damage repair
types II
• Repair of strand breaks (singlestrand breaks occur 10x more
frequently than doubles)
• Limited mitochondrial DNA repair
(nuclear encoded proteins of
OGG1, POLG)
• Nucleotide excision repair (NER)
that is transcription-coupled
repair of active genes
TÁMOP-4.1.2-08/1/A-2009-0011
Genes related to oxidative
DNA damage repair
• Defect is lethal: APE1, FEN1,
POLB, LIG1, LIG3, XRCC1
• Defect is viable: OGG1, NTHL1,
MYH, ADPRT
• Severity not tested: NEIL1, 2, 3,
TDG, SMUG1, APE2
TÁMOP-4.1.2-08/1/A-2009-0011
Oxidative DNA damage repair
and aging
• Elevated cancer frequencies
• Werner syndrome (antirecombinase)
• Cockayne syndrome (TCR)
• XPD and XPA (repair deficiency)
• Base excision repair (BER) defect
is lethal
TÁMOP-4.1.2-08/1/A-2009-0011
Non-oxidative DNA damage
• Depurination and depyrimidination
• Deamination
• Single-strand breaks
• Spontaneous methylation
• Glycation
• Cross-linking
TÁMOP-4.1.2-08/1/A-2009-0011
Non-oxidative protein damage
• Biosynthetic errors
• Transcriptional errors
• Translational errors
• Racemization and isomerization
• Deamidation (asparagine and
glutamine)
• Reactive carbonyl groups (nonoxidative)