PROTEZIONE DEL TELOMERO - Unife
Transcript of PROTEZIONE DEL TELOMERO - Unife
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PROTEZIONE DEL TELOMERO
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The shelterin complex and the structure of telomeres.
Paula Martínez, and Maria A. Blasco J Cell Biol doi:10.1083/jcb.201610111
© 2017 Martínez and Blasco
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mechanism for TRF2-mediated chromosome end protection
GAR domain of TRF2
directly binds to core
histones and that this
interaction is required to
stabilize the chromosome
en
The GAR/Basic domain, located at the N terminus of TRF2, is rich
in Gly/Arg residues and highly
basic
GAR domain of TRF2 directly binds to core
histones and this interaction is required to
stabilize the chromosome end
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GAR domain of TRF2 and core histones.
Akimitsu Konishi et al. J. Biol. Chem. 2016;291:20798-20810©2016 by American Society for Biochemistry and Molecular Biology
basic domain
Conserved arginine residues were changed to alanine or lysine are marked in red
TRF2 RA
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Akimitsu Konishi et al. J. Biol. Chem. 2016;291:20798-20810©2016 by American Society for Biochemistry and Molecular Biology
Rapid telomere DNA loss by loss of histone binding of TRF2.
TRF2 RA
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Akimitsu Konishi et al. J. Biol. Chem. 2016;291:20798-20810©2016 by American Society for Biochemistry and Molecular Biology
Rapid telomere DNA loss by loss of histone binding of TRF2.
TRF2 RA
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Rapid telomere DNA loss by loss of histone binding of TRF2.
Akimitsu Konishi et al. J. Biol. Chem. 2016;291:20798-20810
©2016 by American Society for Biochemistry and Molecular Biology
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MULTIPLE mechanisms for TRF2-mediated chromosome end protection
Suppression of the kinasi ATM activation
the dimerization domain of TRF2 is required to inhibit ATM activation
Inhibits NonHomologousEndJoining
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Genomic DNA isolated from TRF2-proficient (-OHT) or TRF2-null (+OHT) MEFs
Julia Su Zhou Li et al. Science 2017;355:638-641Copyright © 2017, American Association for the Advancement of Science
digested with MboI, pulsed field gel,
radioactive telomeric probe
The zinc finger domains of TZAP directly bind telomeric repeats
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La cromatina telomerica e la sua
modificazione
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Telomeric nucleosomes are hypersensitive to micrococcalnuclease.
Reconstituted nucleosomes on TTAGGG repeats show higher mobility than on other sequences
Telomeric chromatin is enriched for heterochromatin modification, such as tri-methylation of H3K9 and H4K20
Loss of these modifications affects telomere length regulation
Telomeric nucleosomes
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Telomeres also bind to nucleosomes,
which are rich in modified histones.
Major histone modifications found in
telomeres are
-H3K9 and H4K20 trimethylation
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Watson et al., BIOLOGIA MOLECOLARE DEL GENE, Zanichelli editore S.p.A. Copyright © 2005
H3K9
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K
Telomeres in germ and stem cells
Kme3 =trimetillisina
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Telomeres also bind to nucleosomes,
which are rich in modified histones.
Major histone modifications found in
telomeres are
-H3K9 and H4K20 trimethylation
-low abundance of acetylated H3 and
H4
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Berg et al., BIOCHIMICA 6/E, Zanichelli editore S.p.A. Copyright © 2007
Riconoscimento acetilisina
bromodominio
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Watson et al., BIOLOGIA MOLECOLARE DEL GENE, Zanichelli editore S.p.A. Copyright © 2005
Sirtuins play significant roles in the process of aging and also contribute to
the promotion of pulmonary fibrosis.
Sirtuins, initially discovered in the late1980s, are universally known as a
NAD‐dependent histone deacetylases that play a complex role in the process of aging.
Sirtuins are also classified as antiaging molecules; emerging sources of evidence
have shown that these highly conserved enzymes play a pivotal role in pulmonary
fibrosis., ,
Sirtuins are also known as modulators involved in DNA repair, energy metabolism,
apoptosis, and oxidative stress responses., -
Specific members like Sirt2, Sirt6, and Sirt7 regulate inflammation and stress resistance., -
These well‐known mediators of aging also tend to exert protective effects against age‐related diseases such as cancer, diabetes etc, as well as cardiac and liver
fibrosis.
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Watson et al., BIOLOGIA MOLECOLARE DEL GENE, Zanichelli editore S.p.A. Copyright © 2005
Un enzima deacitilante specifico: SIRT6
Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III
deacetylase sirtuin family, which plays a key role in cancer by
controlling transcription, genome stability, telomere integrity, DNA
repair, and autophagy.
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Watson et al., BIOLOGIA MOLECOLARE DEL GENE, Zanichelli editore S.p.A. Copyright © 2005
H3K9
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SIRT6 is a histone H3 lysine 9 deacetylase that
modulates telomeric chromatin
The Sir2 deacetylase regulates chromatin silencing and lifespan in
Saccharomyces cerevisiae.
In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened
lifespan and a premature ageing-like phenotype.
SIRT6 is a chromatin-associated NAD+-dependent, histone H3 lysine 9 (H3K9)
deacetylase that modulates telomeric chromatin.
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SIRT6 is a histone H3 lysine 9 deacetylase that
modulates telomeric chromatin
SIRT6 contributes to the propagation of a specialized chromatin
state at mammalian telomeres,
Deacetilation is required for proper telomere metabolism and
function.
chromatin regulation by SIRT6 is linked to telomere maintenance
and a human premature ageing syndrome
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SIRT6 (sir 2) deacetylates lysine 9 of histone H3 at telomeric chromatin
SIRT6-HY: catalytic H133Y SIRT6 mutant protein
histone tail peptides full-length histone H3 293Tcells
overexpressing SIRT6
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SIRT6 knockdown (S6KD) cells
d, Representative S6KD metaphases showing aberrant telomere signals. Red arrows, sister
telomere loss; blue arrows, telomere doublets. e, Quantification of sister telomere loss
STL
Control
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SIRT6 is a histone H3 lysine 9 deacetylase that
modulates telomeric chromatin
SIRT6 associates specifically with telomeres
SIRT6 depletion leads to telomere dysfunction with end-
to-end chromosomal fusions and premature cellular
senescence.
SIRT6-depleted cells exhibit abnormal telomere
structures
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