Nucleotide Excision Repair: Fighting Cancer & Aging 11η Διημερίδα, ΙΤΕ 2017, 13-14 Οκτωβρίου, Ηράκλειο, Κρήτη

George A. Garinisgarinis@imbb.forth.gr

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

Nucleotide Excision Repair

Kamileri at el., Trends Genetics 2012

Global genome nucleotide excision repair (GG-NER)

RPA

ERCC1XPF

XPGERCC1/XPF

TFIIH

Global genome nucleotide excision repair (GG-NER)

DNA polymerase δ/ε, RFCPCNA and DNA ligase

Global genome nucleotide excision repair (GG-NER)

CSB

RNA polymerase IImRNA

Transcription-coupled nucleotide excision repair (TC-NER)

RPA

XPA

XPG ERCC1/XPF

TFIIH

Transcription-coupled nucleotide excision repair (TC-NER)

DNA polymerase δ/ε, RFCPCNA and DNA ligase

Transcription-coupled nucleotide excision repair (TC-NER)

Nucleotide Excision Repair

Cancer Aging

Heterogeneity

Cancer Ageing

Nucleotide Excision Repair (NER)

Mutations

~30 genes

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

Proc Natl Acad Sci U S A 2012Trends Genetics 2012

NER factors in transcription initiation

Ercc1-/-

Taf10-/-

Taf10-/- and Ercc1-/- mice: striking parallels

Transcription

DNA repair

Tissue-specific NER progeria: adipose tissue

aP2-Ercc1f/-

Wt

AdipocytesWt

Ercc1 -/-

Cre-LoxP Fat-specific Ercc1f/- miceICLs

ERCC1X

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

DNA repairX

Cell metabolism 2013Trends in Immunology 2014

NER factor

Knock-in Transgenic

Bacterial ligaseB

Tagging NER factors in vivo

BioNER mice

FL

B

Peptide

Pup

Fetus

ATRX

SMC3

SMC1

CTCF

MBD2

ERCC1

XPF

?

Gene Silencing

NER factors in mammalian development

Nature Cell Biology 2017

NER factors

“NER does more than its name implies”

3D Chromatin archtecture

& Transcription

Cancer

Progeria

Developmental

abnormalities

DNA repair

DNA damage Gene expression

Garinis lab

Acknowledgements:

Chromatin3DaDDRessCodeAgeMarriAge

ThalisAristeia