Lecture 9 DNA damage Flashcards
Types of DNA damage
Mismatched(methylation, depurination)
DNA breaks- SSB DSb(causes translocation)
Pyrydime Dimers- covalent linkage-UV(TT or CC)
Components
ATM&ATR-transducers
CHK1&CHK2- Mediators
G1/S Phase cycle?
DSB - ATM phospho Chk2
SSB -ATR phospho CHk1
Chk1/2 phospho Cdc25A( degraded)
Cannot remove nibitory phosphates on Cdk2
ATM-ATR phospho p53 and MDM2(E3 Ligase) (stabilizs and accumalates p53)
P53(Transcription F) upregulates p21
P21 Inhibits Cdk2
Intra S Phase?
Extends DNA synthesis(time to repair)
ATM/ATR–Chk2/Chk1–Cdc25A–CDK2 pathway
2nd pathway
ATM/Chk2 phospho NSB1, BRCA19{(breast cancer), SMC1
cascadeG2/M Checkpoint
UV damage- ATR-chk1-Cdc25C
Cdc25/ 14-3-3 protein bind and cytplasmic sequestration
Chk1,Chk2 downregulates Cdc25A and upregulates Wee1
Both control cdc2/cycinB activity
Direct repair
MGMT- methylation(guanine)
MTH1- oxi-free nucleotide to monophosphates.
Base excision Repair
single base(ROS,UV) removed- different DNA glycosylases and AP endonuclease trimmed(not important)- facilitate repair mechanism repaired- DNA pol and XRCC1/ligase
Nucleotide excision repair
Bulky lesions repair recognistion- scanned XPA or stalled ribsome partial unwinding- XPA/RRA/XPC DNA duplex unwound- TF IIH Dual excision- XPF&XPG Repaired- DNA pol
Mismatch Repair
Replication Errors Recognition- MSH2/6 complex Cleaved- recuirment of Mlh1 and Pms2 Removal- Exonuclease Repaired- DNA pol
DBSB- non homologous endjoining
Recognised- Ku70/80
Fixed- DNA ligase IV/XRCC4
Homologous
Rad51- finds copy on sister chromatid
strand invasion-
Therapies
replacement of mutatied TUmour supressor with normal one- RB1&TP53 (hard to find vectors))
Supress oncogene function- complementary mRNA- hard to target everything-resistance
