DNA Mutation & Repair

100 question-and-answer flashcards to review DNA damage types, DNA repair mechanisms (BER, MMR, NER, NHEJ, HR), and cancer-related implications from Foundations of Medicine notes.

What are the two broad categories of DNA damage sources?

Endogenous (inside the body) and exogenous (outside the body).

Define transversion mutation.

A substitution where a purine is replaced by a pyrimidine or vice versa.

Define transition mutation.

A substitution where a purine is replaced by another purine, or a pyrimidine by another pyrimidine.

What is a missense mutation?

A mutation that substitutes one amino acid for another in a protein.

What is a nonsense mutation?

A mutation that creates a premature stop codon.

What is a frameshift mutation?

Insertion or deletion of nucleotides that changes the reading frame.

What is a silent mutation?

A DNA sequence change that does not alter the amino acid sequence.

Name endogenous sources of DNA damage.

Replication errors, chemical instability, deamination, depurination, depyrimidination, and free radicals.

What happens during cytosine deamination?

Cytosine converts to uracil; if unrepaired, GC base pairs can become AT.

What happens when 5-methylcytosine deaminates?

5-methylcytosine deaminates to thymine; contributes to C→T transitions.

What is deamination of adenine?

Adenine deaminates to hypoxanthine.

What is deamination of guanine?

Guanine deaminates to xanthine.

What is depurination?

Hydrolysis of the N-beta-glycosyl bond, creating an apurinic (AP) site.

What is an AP site?

An apurinic/apyrimidinic site lacking a base.

Is depurination more frequent than depyrimidination?

Yes, depurination is more frequent.

What is depyrimidination?

Removal of a pyrimidine base, creating an AP site.

What are free radicals in DNA damage?

Reactive oxygen species that can cause strand breaks and base damage.

Name exogenous sources of DNA damage.

Ionizing radiation, UV radiation, and chemicals.

What does ionizing radiation do to DNA?

Causes double-strand breaks.

What does UV radiation cause in DNA?

Pyrimidine dimers (thymine-thymine dimers) that interfere with replication and transcription.

What is a direct-acting mutagen?

An electrophile that directly modifies DNA bases and distorts base pairing.

Examples of direct-acting mutagens.

EMS, DMS, nitrogen mustards.

What is an indirect-acting mutagen?

A mutagen that requires metabolic activation to become active.

Examples of indirect-acting mutagens.

Benzo[a]pyrene; aflatoxin B1.

What are deaminating agents?

Nitrous acid and related nitrites/nitrosamines.

Examples of nitrosamines.

Nitrosamine compounds; N-nitrosamines.

Examples of nitrites and nitrates.

Sodium nitrite; sodium nitrate (used as preservatives with minimal damage at low levels).

What is the role of nitrites and nitrates in foods?

Used as preservatives; contribution to DNA damage is minimal at low concentrations.

What are alkylating agents?

Chemicals that transfer an alkyl group to DNA.

Name examples of alkylating agents.

S-adenosylmethionine; dimethylnitrosamine; dimethylsulfate; nitrogen mustard.

What does dimethylsulfate do to guanine?

Converts guanine to O6-methylguanine, which cannot base-pair with cytosine.

What is O6-methylguanine?

Guanine methylated at O6; tends to mispair with thymine.

What is nitrogen mustard?

A direct-acting mutagen/carcinogen used in chemotherapy that crosslinks DNA.

What is the role of free radicals in DNA damage?

Cause strand breaks and base modifications via reactive oxygen species.

What is Base Excision Repair (BER)?

Single-strand repair pathway for lesions that do not distort the helix.

When does BER occur?

Throughout the cell cycle.

What lesions does BER repair?

Deaminated C and A; alkylated or oxidized bases; bases with open rings.

List the steps of BER.

DNA glycosylase removes damaged base → AP site; AP endonuclease cuts 5′; AP lyase cuts 3′; DNA polymerase fills; DNA ligase seals.

What is DNA glycosylase?

Removes the damaged base, creating an AP site.

What does AP endonuclease do in BER?

Cuts the backbone on the 5′ side of the AP site.

What does AP lyase do in BER?

Cuts the backbone on the 3′ side of the AP site.

What is the role of DNA polymerase in BER?

Lays down the new bases to replace the removed ones.

What is the role of DNA ligase in BER?

Seals the remaining nick in the backbone.

Why must damaged vs undamaged strand be distinguished in BER?

To identify which strand is correct to use as a template for repair.

What is Mismatch Repair (MMR)?

Repair of base-pair mismatches and small indels missed by DNA polymerase.

When does MMR occur?

During S phase after DNA replication.

What lesions does MMR repair?

Base-pair mismatches and small insertions/deletions.

Which proteins identify errors in MMR?

MSH proteins.

What is the role of endonuclease in MMR?

Cuts the damaged strand.

What is the role of helicase in MMR?

Unwinds DNA to allow exonuclease to remove the damaged segment.

What is the role of exonuclease in MMR?

Removes the damaged segment.

Why is the new strand unmethylated in MMR?

To distinguish it from the old strand for repair.

What is Nucleotide Excision Repair (NER)?

Repair of distortions in the DNA helix (bulky adducts, thymine dimers).

When does NER occur?

In the G1 phase.

What lesions does NER repair?

Bulky DNA lesions and thymine dimers (UV-induced).

Outline the steps of NER.

Large multi-enzyme complex detects distortion; endonucleases remove damaged DNA; DNA polymerase fills; ligase seals.

What is Xeroderma pigmentosum?

Autosomal recessive disorder due to defects in NER; UV sensitivity; skin cancer predisposition; nervous system degeneration.

What is Non-Homologous End Joining (NHEJ)?

DSB repair throughout the cell cycle; end-to-end joining; error-prone.

What are components of NHEJ?

DNA-PK; nucleases; ligases.

What is a consequence of NHEJ?

Deletion of nucleotides; can occur even if ends come from the same chromosome.

Can NHEJ join ends from different chromosomes?

Yes; can result in translocations.

What is Homologous Recombination (HR)?

DSB repair using a homologous sequence as a template (sister chromatid or homologous chromosome).

When does HR occur?

Late S phase or G2.

What serves as a template in HR?

The homologous chromosome or sister chromatid.

What are the steps of HR?

5′ ends are digested by exonucleases; strand invasion; DNA synthesis; Holliday structures form; resolution.

What is a Holliday structure?

A cross-shaped DNA intermediate formed during recombination.

Why is HR considered high-fidelity repair?

Because it uses an accurate homologous template.

What are clinical correlations related to HR?

ATM (Ataxia telangiectasia) and BRCA1/BRCA2 involvement.

What is Ataxia Telangiectasia?

Autosomal recessive disorder due to mutations in ATM gene; broad phenotypes; cancer susceptibility; neurodegeneration.

What is the role of ATM gene?

ATM participates in the homologous recombination DNA repair pathway.

What is BRCA1/BRCA2's role?

Genes involved in HR repair; mutations predispose to cancer.

How does dysfunctional DNA repair relate to cancer?

Predisposes to cancer; mutation rate is at least 1000x higher.

What is the Multi-hit Model?

Multiple mutagenic events over time lead to cancer.

Why would cancer be more common in older individuals?

More time for mutations to accumulate.

What is a pyrimidine dimer?

A covalent link between two pyrimidines (usually thymine) caused by UV light.

What is a thymine dimer?

A thymine-thymine pyrimidine dimer formed by UV exposure.

Where is XP sensitivity most notable?

In sunlight exposure—UV-induced lesions due to NER defects.

What are indirect-acting mutagens exemplified by benzo[a]pyrene and aflatoxin B1?

Indirect-acting mutagens that require metabolic activation.

What is the role of P-450 enzymes in mutagen activation?

Add electrophilic centers to chemicals to form active mutagens.

What is the role of BER in repairing deaminated bases?

BER recognizes and removes the damaged base to initiate repair.

What is the role of BER in repairing oxidized bases?

BER removes oxidized bases and replaces them with correct nucleotides.

What is the main function of MMR after replication?

Corrects base mispairs and small indels missed by DNA polymerase.

What is the main function of NER regarding UV-induced damage?

Remove thymine dimers and bulky helix-distorting lesions.

What type of lesions are targeted by BER and MMR specifically?

BER targets small base lesions; MMR targets mispairs and small indels.

Which repair pathway is active in both S and G2 for DSBs?

HR (Homologous Recombination) is active in late S/G2, after replication.

Which repair pathway is generally more error-prone?

NHEJ.

Which repair pathway uses a sister chromatid as a template?

HR.

What is the primary consequence of defective DNA repair in cancer development?

Increased mutation rate and genomic instability.

What is the role of BRCA1/BRCA2 mutations in cancer predisposition?

Impaired HR repair increases cancer risk.

What is the main role of DNA-PK in DNA repair?

A key kinase in the NHEJ pathway for end-joining.

Which phase is primarily associated with NER?

G1 phase.

What is the significance of the reading frame in mutations?

Frameshift mutations disrupt the reading frame and protein sequence.

What is the effect of UV on DNA transcription and replication?

Thymine dimers hinder replication and transcription.

Why are alkylating agents mutagenic?

They transfer alkyl groups to DNA bases, distorting pairing.

What is the general relationship between DNA repair defects and aging?

Repair defects increase mutation accumulation, contributing to aging and cancer.

What is the clinical significance of Xeroderma pigmentosum beyond cancer risk?

Increased sun sensitivity and nervous system degeneration.

What type of DNA damage is most associated with ionizing radiation?

Double-strand breaks (DSBs).

What distinguishes BER from NER in terms of lesion size?

BER fixes small, non-helix-distorting lesions; NER fixes bulky, helix-distorting lesions.

What is the main purpose of DNA repair pathways?

To maintain genome stability by correcting DNA lesions and preventing mutations.

Which enzyme creates an AP site after base removal in BER?

DNA glycosylase creates the AP site by removing the damaged base.