USMLE PRACTICE QUESTION #126
TOPIC: Mechanisms of DNA damage & repair
USMLE practice question #126 will test your understanding of the mechanisms of DNA damage & repair.
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A 7-year-old boy presents to the pediatric clinic with a history of recurrent skin blistering and ulceration after minimal sun exposure. His parents report that the lesions heal slowly and leave scars. Physical examination reveals hyperpigmented macules and freckling over sun-exposed areas, along with multiple areas of atrophic scarring. Laboratory studies show normal complete blood count and serum electrolytes. Genetic testing identifies a mutation in a gene encoding an endonuclease involved in nucleotide excision repair. Which of the following types of DNA damage is most likely to accumulate in this patient?
A) Double-strand DNA breaks
B) Thymine-thymine dimers
C) 8-oxoguanine residues caused by reactive oxygen species
D) DNA interstrand cross-links
E) Mismatched DNA bases
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following types of DNA damage is most likely to accumulate in this patient?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Diagnose the boy’s condition; 2nd: Identify the likely underlying cause.
Step 3: Read the vignette carefully and ask yourself: “The most likely underlying cause of this boy’s condition is _____________________-.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 7-year-old boy presents with recurrent skin blistering and ulceration after minimal sun exposure, hyperpigmented macules, and atrophic scarring in sun-exposed areas. These findings, along with a mutation in a gene encoding an endonuclease involved in nucleotide excision repair (NER), strongly suggest a diagnosis of xeroderma pigmentosum.
ANSWER CHOICES:
CHOICE A: Double-strand DNA breaks
Explanation: Double-strand DNA breaks can occur due to ionizing radiation or during replication stress. These breaks are repaired by homologous recombination or non-homologous end joining.
CHOICE B: Thymine-thymine dimers
Explanation: UV radiation causes covalent bonding between adjacent thymine bases on the same DNA strand, forming thymine-thymine dimers. These lesions distort the DNA helix and block replication and transcription.
CHOICE C: 8-oxoguanine residues
Explanation: 8-oxoguanine is a form of oxidative DNA damage caused by reactive oxygen species. This lesion is repaired by the base excision repair pathway.
CHOICE D: DNA interstrand cross-links
Explanation: DNA interstrand cross-links are caused by agents like cisplatin or mitomycin C. These lesions prevent strand separation during replication and transcription and are repaired by specialized pathways involving homologous recombination.
CHOICE E: Mismatched DNA bases
Explanation: Mismatched bases arise during DNA replication due to errors made by DNA polymerase. These errors are corrected by the mismatch repair pathway.
FINAL VERDICT…
CORRECT ANSWER: B) Thymine-thymine dimers
Thymine-thymine dimers are the hallmark type of DNA damage caused by UV radiation. In xeroderma pigmentosum, defective nucleotide excision repair prevents the removal of these dimers, leading to their accumulation and subsequent cellular damage in sun-exposed areas.
KEY CONCEPTS:
Xeroderma Pigmentosum (XP):
Rare autosomal recessive disorder caused by mutations in genes involved in nucleotide excision repair.
Leads to defective removal of bulky lesions such as thymine-thymine dimers caused by UV radiation.
Clinical features include photosensitivity, skin blistering, hyperpigmentation, atrophic scarring, and increased risk of skin cancer.
Nucleotide Excision Repair (NER):
Repairs bulky lesions that distort the DNA helix (e.g., thymine dimers).
Steps include recognition of damage, excision of damaged DNA strand by endonucleases, synthesis of new DNA using the undamaged strand as a template, and ligation.
UV-Induced DNA Damage:
UV light causes covalent bonding between adjacent pyrimidines (e.g., thymine-thymine dimers).
If unrepaired, these lesions block replication and transcription, leading to cell death or mutagenesis.
Differential Repair Pathways:
Nucleotide Excision Repair: Repairs bulky lesions like thymine dimers.
Base Excision Repair: Repairs small base modifications like 8-oxoguanine.
Mismatch Repair: Fixes replication errors like mismatched bases.
Homologous Recombination/Non-Homologous End Joining: Repairs double-strand breaks.
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