What are the most common spontaneous chemical reactions damaging DNA?
Depurination and deamination are the most frequent spontaneous DNA-damaging reactions.
How do alkylating agents cause mutations?
They add alkyl groups to DNA bases, leading to mispairing and mutations if not repaired.
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What are the most common spontaneous chemical reactions damaging DNA?
Depurination and deamination are the most frequent spontaneous DNA-damaging reactions.
How do alkylating agents cause mutations?
They add alkyl groups to DNA bases, leading to mispairing and mutations if not repaired.
What are reactive oxygen species (ROS), and how do they affect DNA?
ROS are byproducts of metabolism that cause oxidative DNA damage, leading to mutations and genomic instability.
Define DNA adducts.
A DNA adduct is a segment of DNA that is covalently bonded to a chemical compound.
These adducts form when mutagenic or carcinogenic chemicals bind directly to DNA, potentially leading to mutations and, over time, cancer if not repaired.
What are double-strand breaks (DSBs)?
Breaks affecting both strands of DNA; the most severe form of DNA damage, requiring HR or NHEJ for repair.
What enzyme removes damaged bases in BER?
DNA glycosylase initiates BER by recognizing and excising damaged bases.
What are the two types of NER pathways?
What types of damage activate p53?
various types of cellular stress and DNA damage, including:
DNA Damage
Double-strand breaks (e.g., from radiation)
Single-strand breaks or bulky lesions (e.g., from UV light or chemicals)
Replication stress
Oncogene Activation
Abnormal signals from overactive genes (like Ras or Myc)
Hypoxia
Low oxygen levels in the cell
Telomere Shortening
Critically short telomeres signal aging or damage
Oxidative Stress
Damage from reactive oxygen species (ROS)
What does p53 do after DNA damage?
Once activated, p53 can:
Stop the cell cycle
Repair DNA
Trigger apoptosis (cell death) if damage is severe
Cause senescence (permanent growth arrest)
What is the role of ATM and ATR kinases in DNA repair?
ATM (Ataxia-Telangiectasia Mutated)
Responds to: Double-strand breaks (DSBs)
Activates: p53 and CHK2
Leads to:
Cell cycle arrest
DNA repair (homologous recombination)
Apoptosis if damage is severe
ATR (ATM and Rad3-related)
Responds to: Single-stranded DNA and replication stress
Activates: CHK1
Leads to:
Cell cycle arrest
Stabilization of replication forks
DNA repair (e.g., nucleotide excision repair)
Both activate repair proteins and checkpoints.
What is the G1/S checkpoint's role in DNA repair?
Ensures DNA is intact before replication begins.
How do BER and NER interact?
They can collaborate to repair different types of DNA lesions for more efficient repair.
What are the main repair enzymes?
DNA glycosylases (BER)
Endonucleases (NER, MMR)
DNA polymerases
Ligases
Chromatin remodelers
What is the function of helicases in DNA repair?
Unwind DNA for NER, HR, and at replication forks; ATP-dependent.
What happens during replication fork stalling?
Replication halts due to obstacles (lesions, structures, collisions); restart involves protection proteins and translocases.
What are consequences of replication errors?
Point mutations
Frameshifts
Repeat expansions
Can cause loss of protein function and disease.
Which DNA polymerase is involved in BER?
DNA polymerase β (Pol β) fills the gap after base removal in BER.
What is microsatellite instability (MSI)?
Result of defective MMR leading to errors in repetitive DNA sequences.
What is the role of DNA damage sensors?
Proteins like ATM and ATR detect DNA damage and initiate repair signaling.
What repair defects are seen in neurodegenerative diseases?
Disrupted BER and NER → genomic instability, neuronal dysfunction (seen in Alzheimer’s, Parkinson’s, Huntington’s)
What is translesion synthesis prone to?
It's error-prone; specialized polymerases bypass DNA lesions, often introducing mutations.