Inherited Cancer Syndromes and the DNA Damage Response

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1 Inherited Cancer Syndromes and the DNA Damage Response

2 Inherited Breast Cancer and DNA Double- Strand Break Repair Michal Goldberg Department of GeneGcs The Hebrew University Cancer Hub, March 2014

3 Hallmarks of cancer cells MutaGon accumulagon Chromosomal instability Changes in the structure and number of chromosomes Hanahan and Weinberg. Cell, 2011

4 Hallmarks of cancer cells Hanahan and Weinberg. Cell, 2011

5 DNA damage and DNA repair Damaging agents (internal and external) X- rays Oxygen radicals AlkylaGng agents X DDR UV light AromaGc compounds X- ray RadiomimeGc drugs ReplicaGon errors Collapse of the replicagon fork The DNA damage response Uracil Abasic site 8- Oxoguanine Single- strand break Genomic instability Bulky adduct Thymidine dimers Checkpoint DNA Apoptosis / acgvagon Base- excision repair NucleoGde- excision Senescence repair (BER) repair (NER) Interstrand cross- link Double- strand break Homologous recombinagon Non- homologous end joining Mismatch Inser;on/dele;on Double- strand break Mismatch repair Negri5o. Nature Educa;on 3(9):26

6 DNA damage and DNA repair Damaging agents (internal and external) X- rays Oxygen radicals AlkylaGng agents DDR UV light AromaGc compounds X- ray RadiomimeGc drugs ReplicaGon errors Collapse of the replicagon fork The DNA damage response Uracil Abasic site 8- Oxoguanine Single- strand break Bulky adduct Thymidine dimers Interstrand cross- link Double- strand break Mismatch Inser;on/dele;on Double- strand break Checkpoint DNA Apoptosis / acgvagon Base- excision repair NucleoGde- excision Senescence repair (BER) repair (NER) Homologous recombinagon Non- homologous end joining Mismatch repair Negri5o. Nature Educa;on 3(9):26

7 DNA damage and DNA repair Damaging agents (internal and external) X- rays Oxygen radicals AlkylaGng agents DDR UV light AromaGc compounds X- ray RadiomimeGc drugs ReplicaGon errors Collapse of the replicagon fork The DNA damage response Uracil Abasic site 8- Oxoguanine Single- strand break Bulky adduct Thymidine dimers Interstrand cross- link Double- strand break Mismatch Inser;on/dele;on Double- strand break Checkpoint DNA Apoptosis / acgvagon Base- excision repair NucleoGde- excision Senescence repair (BER) repair (NER) Homologous recombinagon Non- homologous end joining Mismatch repair Negri5o. Nature Educa;on 3(9):26

8 DNA double- strand break (DSB) repair Resec;on of the 5ʹ strands to generate 3ʹ single- stranded DNA HR Homologous recombinagon ; NHEJ Non- homologous end joining ; SSA Single- strand annealing ; BIR break- induced replicagon ; DSBR HR repair ; SDSA Synthesis- dependent strand- annealing Aguilera & Gómez- González, Nat. Rev. Genet (2008)

9 DSB repair and genomic instability Aguilera & Gómez- González, Nat. Rev. Genet (2008)

10 DSB repair and genomic instability Repair impairment Aguilera & Gómez- González, Nat. Rev. Genet (2008)

11 Familial Breast Cancer and DNA DSB Repair

12 Breast cancer suscepgbility genes Apostolou & Fos;ra. Biomed Res Int. (2013)

13 HR repair genes and inherited breast cancer Aguilera & Gómez- González, Nat. Rev. Genet (2008)

14 HR repair genes and inherited breast cancer Zhang & Powell. Mol Cancer Res. (2005) Adapted from: Mladenov et al. Fornt Oncol (2013)

15 Screen for DDR genes involved in estrogen- dependent cancers Genes that are upregulated by estrogen Genes that have a role in the DNA damage response SelecGon for driver mutagons in breast and ovarian cancers Strauss et al. Unpublished Carmit Strauss

16 HR repair genes and inherited breast cancer # Zhang & Powell. Mol Cancer Res. (2005) # Strauss et al. Unpublished BRCA2 = FANCD1 PALB2 = FANCN Adapted from: Mladenov et al. Fornt Oncol (2013)

17 Genes predisposing to breast cancer are mutated in fanconi anemia ICL (interstrand crosslinks) BACH1 = BRIP1 = FANCJ Branzei & Foiani. Nat Rev Mol Cell Biol. (2010)

18 HR repair genes and inherited breast cancer why breast cancer??? Mladenov et al. Fornt Oncol (2013)

19 Estrogen acgvity Droog et al., Eur J Pharmacol. 2013

20 Estrogen- induced DNA repair genes Adapted from: Mladenov et al. Fornt Oncol (2013)

21 Screen for DDR genes involved in estrogen- dependent cancers Genes that are upregulated by estrogen Genes that have a role in the DNA damage response SelecGon for driver mutagons in breast and ovarian cancers Strauss et al. Unpublished Carmit Strauss

22 Estrogen- induced DNA repair genes # # # # # # # Strauss et al. Unpublished Adapted from: Mladenov et al. Fornt Oncol (2013)

23 Estrogen induces DSBs at promoters of estrogen- induced genes Williamson & Lees- Miller. Carcinogenesis (2011)

24 Genomic instability due to DSBs at estrogen- responding genes Inherited mutagon in HR repair gene, regulated by estrogen HR repair gene, regulated by estrogen

25 Genomic instability due to DSBs at estrogen- responding genes Estrogen

26 Genomic instability due to DSBs at estrogen- responding genes Estrogen

27 DNA repair genes and cancer Adapted from: Berger et al., Nature (2011)

28 DNA double- strand break (DSB) repair Aguilera & Gómez- González, Nat. Rev. Genet (2008)

29 Genomic instability due to DSBs at estrogen- responding genes DSB repair Terminal delegon MitoGc recombinagon Small insergon/ delegon or a point mutagon Gene conversion TranslocaGon

30 DNA repair genes and cancer Adapted from: Berger et al., Nature (2011)

31 Genomic instability due to DSBs at estrogen- responding genes DSB repair Terminal delegon Small insergon/ delegon or a point mutagon TranslocaGon

32 HR repair genes and cancer HR repair gene B HR repair gene C Adapted from: Berger et al., Nature (2011)

33 A model: HR repair genes and estrogen- dependent cancers Promotes proliferagon Estrogen Upregulates HR repair gene expression Inherited mutagon (heterozygous) in HR repair gene Genomic instability Estrogen DSB formagon at promoters of E2- upregulated genes

34 HR repair genes and inherited breast cancer Treatment # # Strauss et al. Unpublished Adapted from: Mladenov et al. Fornt Oncol (2013)

35 Single- strand break repair and poly (ADP- ribose) polymerase (PARP) Adapted from: Itamochi, World Biol Chem (2010)

36 Single- strand break repair and poly (ADP- ribose) polymerase (PARP) Adapted from: Itamochi, World Biol Chem (2010)

37 PARP inhibitors Cur;n, Biochem Soc Trans (2014)

38 PARP inhibitors Chen et al, Arch Gynecol Obstet (2013) IV intravenous PO - oral

39 Single- strand break repair and poly (ADP- ribose) polymerase (PARP) PARPi resistance Adapted from: Itamochi, World Biol Chem (2010)

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