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PolyADP ribosylation represents one among many posttranslational modifications of proteins in which polymers are added to protein. -Lipid:Prenylation, Palmitoylation -Peptide:Ubiquitylation, Sumoylation, Neddylation, ISGylation -Carbohydrate:Glycosylation -Nucleotides:PARylation. Nicotina
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1. Parp and Parp inhibitors
2. PolyADP ribosylation represents one among many posttranslational modifications of proteins in which polymers are added to protein.-Lipid:Prenylation, Palmitoylation-Peptide:Ubiquitylation, Sumoylation, Neddylation, ISGylation-Carbohydrate:Glycosylation-Nucleotides:PARylation
3. Nicotinamide Adenine Dinucleotide is the substrate for the reaction.
4. ADP-Ribose
5.
7. PARP=PolyADP-ribose PolymerasePARG=PolyADP-ribose glycohydrolase
13. PARP consists of a family of proteins which has multipe members involved in diverse functions including DNA repair, telomere maintenance,epigenetic regulation and centrosome function.
16. PARP 1 & 2=DNA repairPARP 3=Centrosome functionV-PARP(PARP-4)=Vault particle function(Ribonucleoprotein complexes involved in intracellular transport.Tankyrase 1(TRF1-interacting, ankyrin-related ADP-ribosepolymerase), (PARP-5a)= partner of the human telomeric protein TRF1(telomere repeat binding factor1).Tankyrase 2=Also likely involved in telomere maintenance.
17. PARP-1 constitutes >80% of total intracellular PARP activity;given involvment in DNA repair these two PARPs are likely most relevant to cancer theapeutics.PARP-1 has an automodification Domain.
18. PARPs in DNA repair nd Genome maintenance.
27. CELLS DEFICIENT IN HOMOLOGOUS RECOMBINATION PATHWAYS ARE HYPERSENSITIVE TO PARP INHIBITORS.
29. PARP functions in base excision repair. DNA SSBs form due to oxidative damage and its repair. Inhibition of PARP activity prevents the recruitment of XRCC1 and subsequent SSB gap filling by DNA polymerases. Large numbers of DNA SSBs persist and are encountered by DNA replication forks. These lead to replication fork arrest associated with a DSB. b, In the presence of functional BRCA1 and BRCA2, the proximity of an undamaged sister chromatid template to the DSB allows the invasion of the sister chromatid by a RAD51-coated single-stranded DNA filament, and initiation of sister chromatid recombination repair. This is associated with the formation of nuclear RAD51 foci. A collapsed replication fork may be restarted by this mechanism. c, When Holliday junctions at recombination intermediates are resolved, a sister chromatid exchange may occur. The excess number of replication fork arrests associated with loss of PARP function leads to an increase in sister chromatid recombination events and sister chromatid exchanges. d, In the absence of functional BRCA1 or BRCA2, sister chromatid recombination and the formation of RAD51 foci are severely impaired. Replication-associated DSBs cannot be repaired by sister chromatid recombination. Some remain unrepaired as chromatid breaks but many are repaired by error-prone RAD51-independent mechanisms such as non-homologous end joining (NHEJ) and single-strand annealing (SSA). These cause complex chromatid rearrangements. These cells arrest at the G2/M checkpoint and permanently arrest or undergo apoptosis. PARP functions in base excision repair. DNA SSBs form due to oxidative damage and its repair. Inhibition of PARP activity prevents the recruitment of XRCC1 and subsequent SSB gap filling by DNA polymerases. Large numbers of DNA SSBs persist and are encountered by DNA replication forks. These lead to replication fork arrest associated with a DSB. b, In the presence of functional BRCA1 and BRCA2, the proximity of an undamaged sister chromatid template to the DSB allows the invasion of the sister chromatid by a RAD51-coated single-stranded DNA filament, and initiation of sister chromatid recombination repair. This is associated with the formation of nuclear RAD51 foci. A collapsed replication fork may be restarted by this mechanism. c, When Holliday junctions at recombination intermediates are resolved, a sister chromatid exchange may occur. The excess number of replication fork arrests associated with loss of PARP function leads to an increase in sister chromatid recombination events and sister chromatid exchanges. d, In the absence of functional BRCA1 or BRCA2, sister chromatid recombination and the formation of RAD51 foci are severely impaired. Replication-associated DSBs cannot be repaired by sister chromatid recombination. Some remain unrepaired as chromatid breaks but many are repaired by error-prone RAD51-independent mechanisms such as non-homologous end joining (NHEJ) and single-strand annealing (SSA). These cause complex chromatid rearrangements. These cells arrest at the G2/M checkpoint and permanently arrest or undergo apoptosis.
30. Over activation of PARP causes depletion of cellular NAD leading to depletion of cellular ATP in an effort to regenerate NAD and eventually cellular necrosis.
34. Therefore if a chemotherapeutic regimen is dependent on programmed cell necrosis for efficacy or if the tumour cells have lost crtical pro-apoptotic pathways by mutation, it is possible(purely theoretically) that a PARP inhibitor could blunt its effect.
35. If the chemotherapy works primarily by inducing apoptosis or if the cells themselves have intact apoptotic pathways, due to enhancement of DNA damage and sensitization to DNA damaging agents PARP inhibitors may enhance the efficacy of cytotoxic chemotherapy.
36. Decreased ATP depletion in response to DNA damaging agents may protect certain tissues.
40. Limitation of myocardial and neuronal damage by PARP inhibitors, possibly by limiting ATP depletion in response to DNA damage may reduce chemotherapy induced damage to permanent tissues allowing higher doses to be used.
41. PARP inhibitors may reduce the inflammatory response to DNA damage thus reducing constitutional side effects, possibly nausea.
45. A phase I trial of a PARP inhibitor(NEJM Volume361:123-134)
50. Summary:PARP inhibitors likely work by enhancing DNA damage in cancer cells.(Epigenetic effects not ruled out).Decreased programmed cell necrosis but enhanced apoptosis is likely when PARP inhibitors are used.Future studies may have to stratify patients by mutation status for DNA damage sensors and pro-apoptotic proteins.PARP inhibitors may reduce tissue damage to certain non-dividing tissues.PARP inhibitors alone are toxic to cells deficient/defective in Homologous recombination