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Nucleotide Excision Repair: Fighting Cancer & Aging 11η Διημερίδα, ΙΤΕ 2017, 13-14 Οκτωβρίου, Ηράκλειο, Κρήτη
George A. [email protected]
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DNA damage
G
G
TT
TT
G*G
G
Endogenous:
ROS, alkylation
Exogenous:
UV, chemicals
DNA repair systems
DNA mis-replication
Mutations
Cancer
Blocked transcription
Cell cycle arrest
Aging
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Nucleotide Excision Repair
Kamileri at el., Trends Genetics 2012
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Global genome nucleotide excision repair (GG-NER)
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RPA
ERCC1XPF
XPGERCC1/XPF
TFIIH
Global genome nucleotide excision repair (GG-NER)
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DNA polymerase δ/ε, RFCPCNA and DNA ligase
Global genome nucleotide excision repair (GG-NER)
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CSB
RNA polymerase IImRNA
Transcription-coupled nucleotide excision repair (TC-NER)
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RPA
XPA
XPG ERCC1/XPF
TFIIH
Transcription-coupled nucleotide excision repair (TC-NER)
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DNA polymerase δ/ε, RFCPCNA and DNA ligase
Transcription-coupled nucleotide excision repair (TC-NER)
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Nucleotide Excision Repair
Cancer Aging
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Heterogeneity
Cancer Ageing
Nucleotide Excision Repair (NER)
Mutations
~30 genes
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Nature 2007PLoS Biology
Ercc1-/- XpdTTD
Premature ageing
Developmentaldefects
Skin cancer
DNA damage
Xpc-/-
PLoS Genetics 2008Nature Cell Biol 2009Nature Cell Biol 2008
EMBO J 20052007
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Proc Natl Acad Sci U S A 2012Trends Genetics 2012
NER factors in transcription initiation
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Ercc1-/-
Taf10-/-
Taf10-/- and Ercc1-/- mice: striking parallels
Transcription
DNA repair
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Tissue-specific NER progeria: adipose tissue
aP2-Ercc1f/-
Wt
AdipocytesWt
Ercc1 -/-
Cre-LoxP Fat-specific Ercc1f/- miceICLs
ERCC1X
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x1000
5-m
o1
.5m
o-
x 0005
B.aP2-Ercc1
-/-aP2-Ercc1
+/-
aP2-Ercc1-/- i. ii.
iv.iii.W
AT
DNA damage
Fat degeneration
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DNA repairX
Cell metabolism 2013Trends in Immunology 2014
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NER factor
Knock-in Transgenic
Bacterial ligaseB
Tagging NER factors in vivo
BioNER mice
FL
B
Peptide
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Pup
Fetus
ATRX
SMC3
SMC1
CTCF
MBD2
ERCC1
XPF
?
Gene Silencing
NER factors in mammalian development
Nature Cell Biology 2017
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NER factors
“NER does more than its name implies”
3D Chromatin archtecture
& Transcription
Cancer
Progeria
Developmental
abnormalities
DNA repair
DNA damage Gene expression
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Garinis lab
Acknowledgements:
Chromatin3DaDDRessCodeAgeMarriAge
ThalisAristeia