O2
OH
~ 7 lesions cell / minute
Consequences of Genome (in)stability
Cell survival
Cancer
Cell death
Degenerative Disease & Ageing
single-strand break repair nucleotide excision repair Double-strand break repair
OH
YTop1
P
5’
5’OH
YTop1
P
5’
5’P
OH
End Processing
Gap Filling
Ligation
DNA Repair
Damage Detection PARP
Lig3 XRCC1
OH P PNK Polβ
5’ 3’
APTXTDP1
Lig3 XRCC1 Lig1 PCNA
Lig3 XRCC1Polβ
Lig1 PCNAPolβ Polδ/ε Fen1
Short-patch long-patch
Spinocerebellar Ataxia with Axonal Neuropathy-1 (SCAN1)
cerebellar degeneration
pathology largely restricted to nervous system (no predisposition to cancer)
spinocerebellar ataxia
variable onset (~15 yrs)
SCAN1 AOA1 Normal
Top2
OH
Y
5’5’
YOHP
POH
Y
Top1
P5’5’
OHY
Top1
P5’5’
P OH
El-Khamisy et al., Nature 2005
TDP1 TDP2
Ledesma & El-Khamisy et al. Nature 2009
Ahel & El-Khamisy et al., Nature 2007 El-Khamisy, EMBO Mol Med 2011
?
Top2
OH
Y
5’5’
YOHP
P
TDP2
PDBs arising from TDP2 defect also cause neurodegeration
PDBs arising from TDP2 defect also cause neurodegeration
TDP2
Absence of TDP2 activity in Irish and Egyptian patients harbouring homozyous truncation mutations in TDP2
Y-P P
Y-P P
B UC IV-9 E B UC IV-9 E
P
Y I
* P
Y I
*
OHY
Top1
P5’5’
OHY
Top1
P5’5’
P OH
*
5’
*
3’Top2
OH
Y
5’5’
YOHP
P
TDP1TDP2
Do PDBs arising from TDP2 defect also cause neurodegeration ?
> 5 0 o f t h e deregulated genes a r e a s s o c i a t e d with neurological disease in humans
Gómez-Herreros, …..El-Khamisy, Nature Gent 2014
Does defective PDB repair (in the nervous system) trigger hallmarks of Ageing (systemically) ?
Ageing Somatic
maintenance
Growth
GH#/#IGF'1#
Caroll, Chiang …..El-Khamisy, Hum Mol Gent 2015
New tools for genome editing Clustered Regularly Interspaced Short Palindromic Repeats
(CRISPR)
New tools for genome editing Clustered Regularly Interspaced Short Palindromic Repeats
(CRISPR)
Consequences of Genome (in)stability
Cell survival
Cancer
Cell death
Ashour, Atteya, and El-Khamisy, Nature Rev Cancer 2015
Damage the genome
Chemotherapy and radiotherapy
Synthetic Lethality
“The exploitation of genetic defects essential for tumour cell survival by combining the defect in an affected pathway with a pharmacologically induced defect in a compensatory pathway”
Pearl et al., Nature Rev Cancer. March 2015, doi:10.1038/nrc3891
DDR Cancer Signatures
Pearl et al., Nature Rev Cancer. March 2015, doi:10.1038/nrc3891
DDR Cancer Signatures
Copy Number variations (CNVs)
26
Success in Personalised Therapy Synthetic Lethality
HRerror-free
collapsed replication fork
PARPinhibition
PARP
SSB repair
Cell Death
Pharmaco
logic
Gen
etic
BRCA2-/- sensitive to PARP inhibitors
BRCA2+/- insensitive to PARP inhibitors
In clinical use….Highly specific
No need for other DNA damaging agents PARP knockout mice are healthy
Olaparib (AZD-‐2281) has been approved by the FDA in Dec 2014
The Road Ahead >>>> The Future for S.L.
Pearl et al., Nature Rev Cancer. March 2015, doi:10.1038/nrc3891
Thank You !
University of Sussex, UK Roger Philips, Alan Lehmann, Keith Caldecott, Louise Serpel, Penny Jeggo, Majid Hafezparast
University of Birmingham, Jo Morris
St Jude Hospital, USA Peter Mckinnon, Sachin Katyal
Newcastle University, UK Robert Lightowlers, Martin Meagher
Leiden University, Netherlands Leon Mullenders, Saskia Lagerwerf
Institute of Mol. Biology, Fleming, Greece Maria Fousteri
University of Surrey, UK Lisi Meira
Beatson Institute for Cancer Research, University of Glasgow, UK Anthony Chalmers
BARTS CRUK Peter SchmidtNHS Trust, UK Duncan Gilberts
The Netherland Cancer Institute, Amsterdam, Netherlands Conchita Vens
Drug Discovery, University of Sussex, Simon Ward Richard Angell
Institute for Biomedicine, Barcelona , Spain Travis Stracker
Yale University, USA Joann Sweasy
Past Lab Members Jessica Hudson Cornelia Meisenberg Meryem Alagoz Jean Carroll Chris Rockyard Owen Well Kay Osborn Abhishek Sharma Poorvi Patel Limei Ju
Current Lab Members Mohamed Ashour Lamia El-Shafei Reham Atteya Walaa Ramadan Waheba Elsayed Asmaa Abosoud Mohamed Kamel Menna El-Serafy
Department of Human Genetics, Nijmegen, The Netherlands. Janneke H M Schuurs-Hoeijmakers
Royal College of Surgeons, Dublin, Ireland Mark McCormack
Zewail City, Egypt Nehal Sabry Mohamed Ashour
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