Lecture 10: DNA Damage and Repair Flashcards
How many DNA damaging and replication errors occur per cell per day?
20,000 DNA damaging events
> 10,000 replication errors
How does genomic instability link to cancer?
- subtle changes in sequence - eg Ras
- Dramatic karyotypic changes - gains and losses of complete or partial chromosomes, chromosomal rearrangements
What are some of the major sources of DNA damage?
Radiation: UV (SSB), ionising (DSB and SSB)
Chemicals: alkylating agents (SS), blemycin and oxidative free radicals (SSB, DSB)
Replication errors (SS mismatches, deletions, and insertions
Endogenous DNA enzyme errors: V(D)J recombination (SSB & DSB), Class switch recombination (DSB), other enzymes (SSB & DSB)
What are the major types of DNA repair
- Excision repair: Base excision repair (BER), Nucleotide excision repair (NER)
- Mismatch repair (MMR)
- Double stranded break repair: Homologous recombination (HR), Non-homologous DNA end joining (NHEJ)
what are the DNA repair pathways in humans?
Wood et al 2001 - >100 genes likely participate in these processes
How do human diseases link to defects in DNA repair systems?
Hereditary cancers:
1. DSB repair - various cancers
2. NER - Xeroderma pigmentosum (Skin and brain)
3. MMR - hereditary nonpolyposis colon cancer (or Lynch syndrome)
How is hereditary nonpolyposis colon cancer (HNPCC) linked to MMR?
- 1990s - sporadic (non-familial) colorectal cancers showed high freq of alterations in poly(A) tracts in their genomes
- Similar changes occur in other repeats - typically <6bp repeats
- ” Microsatellite instability” occurs for most people with HNPCC
How is DNA damage linked to apoptosis
- If DNA damage is too great cells can decide wither to repair their DNA or not
- Failure to therefore kill the cell would lead to oncogenesis
- The relationship between DNA repair and apoptosis is intricate:
proteins detect DNA dam can communicate directly to apoptotic machinary
Apoptosis regulators such as Bcl2 can participate in regulation of repair
Oncogeneic kinases can inhibit apoptosis and DNA repair
What is the role of p53?
“gaurdian of the genome”
It is a gatekeeper AND caretaker gene
What are gatekeeper genes?
genes that control cell proliferation and death
What are caretaker genes?
genes whose inactivation leads to genetic instability
What is the link between cancer therapy and DNA damage?
- Ionising radiation and chemotherapy
- These effect all dividing cells, especially cancers because they divide rapidly
- now clear that some cancer therapies work becauses they indue a large amount of DNA damage
- cells cannot repair such large amounts leading to apoptosis
What is the link between cancer therapy and DNA damage?
- Ionising radiation and chemotherapy
- These effect all dividing cells, especially cancers because they divide rapidly
- now clear that some cancer therapies work becauses they indue a large amount of DNA damage
- cells cannot repair such large amounts leading to apoptosis
What are potential problems with cancer therapies
therapy may induce a response such that cancerous cells do not enter apoptosis but healthy cells DO
This can ake tumours resistance to drugs leading to increased proportion of cancer cells
What are the tfuture advances of cancer therapies
Identification of varieations in different tumours may enable treatments to be tailored to specific individuals
P53 mutant - activate mutant or add functional gene mimic downsteam effects
p53 wild type - activate p53 repsoense
