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