PROTEZIONE DEL TELOMERO - Unife

PROTEZIONE DEL TELOMERO

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

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

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


Rapid telomere DNA loss by loss of histone binding of TRF2.

TRF2 RA



TRF2 RA


Akimitsu Konishi et al. J. Biol. Chem. 2016;291:20798-20810

©2016 by American Society for Biochemistry and Molecular Biology

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

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

La cromatina telomerica e la sua

modificazione

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

Telomeres also bind to nucleosomes,

which are rich in modified histones.

Major histone modifications found in

telomeres are

-H3K9 and H4K20 trimethylation

Watson et al., BIOLOGIA MOLECOLARE DEL GENE, Zanichelli editore S.p.A. Copyright © 2005

H3K9

K

Telomeres in germ and stem cells

Kme3 =trimetillisina

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

Berg et al., BIOCHIMICA 6/E, Zanichelli editore S.p.A. Copyright © 2007

Riconoscimento acetilisina

bromodominio


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.


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.


H3K9

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.



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

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

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



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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