Question

A patient develops skin cancer and worsening hyperpigmentation following sun exposure. Which DNA repair pathway is most likely impaired?

• A. Nucleotide excision repair
• B. Base excision repair
• C. Non-homologous end joining (NHEJ)
• D. Mismatch repair

Hint:

UV-induced thymine dimers are repaired by nucleotide excision repair. Defect causes xeroderma pigmentosum.

Answer 1

The Correct Option is A

Step 1: Understanding the Question:
The clinical triad of extreme photosensitivity, early-onset skin malignancies, and progressive hyperpigmentation (freckling) in sun-exposed areas is the classic presentation of Xeroderma Pigmentosum (XP).
This condition is a prototype for understanding how cells manage bulky DNA damage caused by external environmental factors like Ultraviolet (UV) radiation.
Step 2: Detailed Explanation:

Mechanism of UV Damage: When skin is exposed to UV light (particularly UV-B), it triggers the formation of pyrimidine dimers, such as thymine-thymine dimers. These dimers create bulky covalent adducts that distort the DNA double helix, obstructing both DNA replication and transcription.

Nucleotide Excision Repair (NER) Pathway: This is the primary mechanism for repairing such bulky, helix-distorting lesions. The process follows a structured sequence:

Recognition: Specialized proteins (XPC) identify the physical distortion in the DNA backbone.

DNA Unwinding: The TFIIH complex, containing helicases like XPB and XPD, unwinds the DNA around the lesion site.

Incision and Excision: Endonucleases (XPF and XPG) cleave the damaged strand at specific distances (approximately 24–32 nucleotides apart), effectively removing the damaged segment.

Resynthesis and Ligation: DNA Polymerase fills the resulting gap using the undamaged template strand, and DNA Ligase seals the remaining nick to restore the DNA backbone.


Xeroderma Pigmentosum Pathophysiology: XP is an autosomal recessive disorder caused by mutations in any of the genes encoding these NER proteins (XPA through XPG). Since the repair mechanism is non-functional, pyrimidine dimers accumulate, leading to a massive increase in the mutation rate and subsequent skin cancers.

Analyzing Alternative Repair Pathways:

Base Excision Repair (BER): Primarily repairs non-bulky damage like deaminated or oxidized bases; it does not process pyrimidine dimers.

Mismatch Repair (MMR): Corrects replication errors (mismatches); defects lead to Lynch Syndrome.

Non-homologous end joining (NHEJ): Repairs double-strand breaks; defects lead to SCID or ataxia-telangiectasia.


Step 3: Final Answer:
The inability to repair UV-induced pyrimidine dimers due to an impaired Nucleotide Excision Repair (NER) pathway is the fundamental defect in this patient's condition.