Note for: Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy
Note: Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy
(doi: 10.1016/j.chembiol.2017.08.027)
Process that maintain genome integrity in normal cells - it will help cancer to develop resistance to radiation and DNA-damaging chemotherapeutics.
New target;
RAD51 recombinase, RAD52, and MRE11 nuclease, WRN DNA helicase.
Synthetic lethality - two individual mutations but when combined resulting in lethal phenotype.
Hartwell, is the first guy who initiated the synthetic lethality with the cancer baring the DNA-repair proteins defect. Also, cancer that addict to particular DNA repair mechanism.
Therefore, the target for synthetic lethality is that finding the protein that the cancer cell relied on for viability (but less important in normal cell) and inhibit theirs function.
Synthetic lethality; two types
1.between-pathway (each backup for each other)
2.In-pw synthetic lethality, mutation either way of reversible step --> still survive but if additionally blocks the reverse way --> become lethal.
This robustness also represents an Achilles’ hill of the cancerous cell that can be exploited for therapeutic purposes.
BRCA1 and BRCA2 -- tumor suppressors, commonly mutated or downregulated in hereditary/sporadic breast and ovarian cancers.
Both proteins play role in DSB repair, protein-DNA crosslinks, and collapsed replication forks.
BRCA1 -- regulates DNA repair pw choice at DSB - promoting homology directed DNA repair (HDDR) over NHEJ, also over mutagenic single-strand annealing (SSA).
BRCA2 - recombination mediator, facilitate assembly of RAD51 to ssDNA.
13 tumor suppressor that interacting with BRCA1 and BRCA2 (these two are very important that it played role in resistant).
PARP1 - enzyme adding the sugar to the protein for signaling the DNA dmage (PARylation); responsible BER which is induced by ROS or abortive TOPI.
PARP1 is activated by the "DNA lesions" which are DSB, SSB and DNA crosslinks, and stalled replication forks.
Auto-PARylation will cause PARP1 becoming negative and then PARP1 will detach from DNA.
Parp-1 is the good target;
1. it slows down the replication folk when there is the lesion, therefore the cell goes through the HR once there is the replication.
2. widening the therapeutic window, by which we know that cancer cells divide rapidly therefore, it tends to entering to S-phase more often than the normal cells -- it is good for the cancer that lacks HR.
After activation, it reorganized chromatin around DNA lesion which later DNA repair will be initiated.
Generation of parp1,
1.inhibit the active site of Parp1
2.inhibit dissociation of parp1 from the DNA damage site (protein-DNA trapping)
Tumor that acquired resistant -- shown to have accumulation of mutation in BRCA1/BRCA2 that can restore HR activity.
HR can be restored in BRCA1 mutated cell by the loss of 53BP1 function. Also, the hypomorph version of BRCA1 (hypomorph: a mutant gene having a similar but weaker effect than the corresponding wild-type gene - wiki search) -- showed resistant to PARP inhibitor.
With the Parp1 inhibitor; it is very useful to study the DNA repair mechanisms regulated by PARylation. REQ1 is regulated by Parp1.
There is the study on HTC of Rad54 on holliday junction migration.
WRN inhibition - sensitizes cancer cells to DNA cross-linking agent MMC.
FA is used for fixing the ICLs and protein-DNA crosslinks in higher eukaryotes. Therefore, it helps DNA replication as well as transcription runs smoothly.
Below is the challenges that the cell will use FA to fix the lesion;
Exogenous challenges -- MMC cisplatin, melphalan
Endogenous challenges -- lipid peroxidation, ethanol metabolism, nitric oxide.
MRE11 has 3'-5' exonuclease activity and endonuclease activity directed to ssDNA and hairpin dsDNA -- process that irreversibly commits DSB to HDDR.
Besides Parp inhibitor; more attempt to search for another target for synthetic lethality to treat cancer with defective in HR.
There is the gap how Rad52 becoming synthetic lethality with cancer cells defective intumor suppressors BRCA1, BRCA2 or PALB2 -- the authors mentioned this is due to the lack of information on Rad52 function in human cell.
Reason to give Rad51 is the attractive target;
1. Rad51 -central player of Rad51 and repairing stalling lesions that are caused by DNA-damaging cancer treatments
2.Inhibit the central step not the initial step which could then switch to NHEJ
3.Higher in Rad51 are found in different cancers that showed to have resistance to radiation and chemotherapy - also there is the evident showing reduction of Rad51 could overcome such resistant.
With a good successful in synthetic therapy by using PARPi with the HR-defective cancer, there are more attempt to identify the new target as well as a new adjuvants to treat with conventional therapy like radiation and DNA damaging chemotherapies.
Major obstacles that the authors raised in discovering and developing small molecule effectors -- we are aiming to disrupting the interaction between macromolecules; these could be either protein-protein or DNA-protein interaction. This is the area which is hard by itself.
Besides the PARP1-inhibitors, the author suggested on Rad52 and Rad51 which could be the good target to develop the inhibitor to those targets.
(doi: 10.1016/j.chembiol.2017.08.027)
Process that maintain genome integrity in normal cells - it will help cancer to develop resistance to radiation and DNA-damaging chemotherapeutics.
New target;
RAD51 recombinase, RAD52, and MRE11 nuclease, WRN DNA helicase.
Synthetic lethality - two individual mutations but when combined resulting in lethal phenotype.
Hartwell, is the first guy who initiated the synthetic lethality with the cancer baring the DNA-repair proteins defect. Also, cancer that addict to particular DNA repair mechanism.
Therefore, the target for synthetic lethality is that finding the protein that the cancer cell relied on for viability (but less important in normal cell) and inhibit theirs function.
Synthetic lethality; two types
1.between-pathway (each backup for each other)
2.In-pw synthetic lethality, mutation either way of reversible step --> still survive but if additionally blocks the reverse way --> become lethal.
This robustness also represents an Achilles’ hill of the cancerous cell that can be exploited for therapeutic purposes.
BRCA1 and BRCA2 -- tumor suppressors, commonly mutated or downregulated in hereditary/sporadic breast and ovarian cancers.
Both proteins play role in DSB repair, protein-DNA crosslinks, and collapsed replication forks.
BRCA1 -- regulates DNA repair pw choice at DSB - promoting homology directed DNA repair (HDDR) over NHEJ, also over mutagenic single-strand annealing (SSA).
BRCA2 - recombination mediator, facilitate assembly of RAD51 to ssDNA.
13 tumor suppressor that interacting with BRCA1 and BRCA2 (these two are very important that it played role in resistant).
PARP1 - enzyme adding the sugar to the protein for signaling the DNA dmage (PARylation); responsible BER which is induced by ROS or abortive TOPI.
PARP1 is activated by the "DNA lesions" which are DSB, SSB and DNA crosslinks, and stalled replication forks.
Auto-PARylation will cause PARP1 becoming negative and then PARP1 will detach from DNA.
Parp-1 is the good target;
1. it slows down the replication folk when there is the lesion, therefore the cell goes through the HR once there is the replication.
2. widening the therapeutic window, by which we know that cancer cells divide rapidly therefore, it tends to entering to S-phase more often than the normal cells -- it is good for the cancer that lacks HR.
After activation, it reorganized chromatin around DNA lesion which later DNA repair will be initiated.
Generation of parp1,
1.inhibit the active site of Parp1
2.inhibit dissociation of parp1 from the DNA damage site (protein-DNA trapping)
Tumor that acquired resistant -- shown to have accumulation of mutation in BRCA1/BRCA2 that can restore HR activity.
HR can be restored in BRCA1 mutated cell by the loss of 53BP1 function. Also, the hypomorph version of BRCA1 (hypomorph: a mutant gene having a similar but weaker effect than the corresponding wild-type gene - wiki search) -- showed resistant to PARP inhibitor.
With the Parp1 inhibitor; it is very useful to study the DNA repair mechanisms regulated by PARylation. REQ1 is regulated by Parp1.
There is the study on HTC of Rad54 on holliday junction migration.
WRN inhibition - sensitizes cancer cells to DNA cross-linking agent MMC.
FA is used for fixing the ICLs and protein-DNA crosslinks in higher eukaryotes. Therefore, it helps DNA replication as well as transcription runs smoothly.
Below is the challenges that the cell will use FA to fix the lesion;
Exogenous challenges -- MMC cisplatin, melphalan
Endogenous challenges -- lipid peroxidation, ethanol metabolism, nitric oxide.
MRE11 has 3'-5' exonuclease activity and endonuclease activity directed to ssDNA and hairpin dsDNA -- process that irreversibly commits DSB to HDDR.
Besides Parp inhibitor; more attempt to search for another target for synthetic lethality to treat cancer with defective in HR.
There is the gap how Rad52 becoming synthetic lethality with cancer cells defective intumor suppressors BRCA1, BRCA2 or PALB2 -- the authors mentioned this is due to the lack of information on Rad52 function in human cell.
Reason to give Rad51 is the attractive target;
1. Rad51 -central player of Rad51 and repairing stalling lesions that are caused by DNA-damaging cancer treatments
2.Inhibit the central step not the initial step which could then switch to NHEJ
3.Higher in Rad51 are found in different cancers that showed to have resistance to radiation and chemotherapy - also there is the evident showing reduction of Rad51 could overcome such resistant.
With a good successful in synthetic therapy by using PARPi with the HR-defective cancer, there are more attempt to identify the new target as well as a new adjuvants to treat with conventional therapy like radiation and DNA damaging chemotherapies.
Major obstacles that the authors raised in discovering and developing small molecule effectors -- we are aiming to disrupting the interaction between macromolecules; these could be either protein-protein or DNA-protein interaction. This is the area which is hard by itself.
Besides the PARP1-inhibitors, the author suggested on Rad52 and Rad51 which could be the good target to develop the inhibitor to those targets.
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