Lecture 18: DNA Repair

A set of practice flashcards covering DNA damage types, repair pathways (BER, NER, NHEJ, HR), and associated diseases and treatments discussed in Lecture 20.

Why is DNA the only biological macromolecule that is repaired rather than replaced?

Because DNA encodes the genetic instructions used in the development and functioning of all known living organisms, making its stability essential for cell survival.

What are the three main endogenous sources of DNA damage mentioned in the lecture?

Hydrolysis, reactive oxygen species, and by-products of metabolism.

Identify four exogenous sources that cause reactions with DNA molecules from outside the cell.

UV light, X-rays, carcinogens, and chemotherapeutics.

Which type of mutation is generally more likely to occur: transitions or transversions?

Transitions are more likely because substituting one double ring structure for another (or single for single) is more probable than substituting a double ring for a single ring.

Approximately how many depurination events occur per genome per day?

Approximately $18,000$ per genome per day.

What is the standard estimated number of total DNA lesions generated per cell per day?

$$100,000/\text{day}$$

What specific type of mutation is often the result of an abasic (AP) site, making it potentially very damaging?

A frameshift mutation.

How does UV light physically affect the DNA helix?

It induces the formation of pyrimidine dimers that join bases together, distorting the DNA and reducing its flexibility.

Why are interstrand DNA crosslinks and DNA-protein crosslinks considered highly toxic to the cell?

They are highly toxic because they block the essential processes of replication and transcription.

Provide three examples of inducers that cause double-strand breaks (DSBs).

X-rays, Ionising radiation, and Topoisomerase II inhibitors.

Provide three examples of inducers that cause single-strand breaks (SSBs).

Reactive oxygen species, Hydroxyurea, and Camptothecin.

Which specific repair pathway is used for base damage such as deamination or abasic sites?

Base excision repair (BER).

What strategy does Base Excision Repair (BER) use to identify errors in the DNA?

A base-flipping strategy to identify deaminated bases (e.g., Uracil).

Which enzymes are responsible for removing the sugar-phosphate during Base Excision Repair?

AP endonuclease and phosphodiesterase.

When is the Nucleotide Excision Repair (NER) pathway used?

NER is used when more than one base is involved in the damage, such as pyrimidine dimers caused by UV light.

What are two major deficiencies of translesional DNA polymerases?

They lack precision in template recognition/substrate base choice and they lack exonucleolytic proof-reading activity.

In which phase of the cell cycle is Non-homologous end joining (NHEJ) primarily restricted?

The $\text{G1}$ phase.

Why is Non-homologous end joining (NHEJ) considered an error-prone repair mechanism?

Because it usually results in the loss of nucleotides surrounding the break site, meaning important genetic information may be lost.

When does Homologous Recombination (HR) occur and what does it use as a template?

It occurs only in $\text{S-phase}$ and uses an intact sister chromatid as a template for error-free repair.

What are the three locations in the cell cycle where DNA damage is detected to stop progression?

(i) $\text{G1}$, (ii) Entry to $\text{S-phase}$, and (iii) Entry into mitosis.

How does the protein $\text{p21}$ prevent cell cycle progression during DNA damage?

$\text{p21}$ is activated by $\text{p53}$ and renders the $\text{G1/S-CDK}$ and $\text{S-CDK}$ complexes inactive.

What is the cellular outcome if DNA damage is not possible to repair?

Apoptosis (cell death).

Which DNA repair process is affected in patients with Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer)?

Mismatch repair (affected genes include $\text{MSH2}$, $\text{MSH3}$, $\text{MSH6}$, $\text{MLH1}$, and $\text{PMS2}$).

What is the prevalence of Xeroderma Pigmentosum (XP) in Japan?

$1$ in $40,000$

What is the increased risk factor for skin cancer in individuals with Xeroderma Pigmentosum?

A $2000$-fold increased risk.

What percentage of inherited breast cancers are associated with $\text{BRCA1}$ or $\text{BRCA2}$ mutations?

$80-90$ percent.

What is the lifetime risk of developing breast cancer for a $\text{BRCA1/2}$ carrier?

$80$ percent.

What three characteristics are exhibited by $\text{BRCA2}$ deficient cells?

They exhibit genomic instability, are sensitive to DNA damaging agents, and are defective in Homologous Recombination (HR).

What clinical drug is used to treat $\text{BRCA2}$-deficient tumors by utilizing the concept of synthetic lethality?

Lynparza (Olaparib), which is a PARP (poly(ADP-ribose) polymerase) inhibitor.

Which specific process is defective in Fanconi anemia groups A-G?

DNA interstrand cross-link repair.