A patient presents with skin cancer and hyperpigmentation that worsens with sunlight exposure. Which of the following DNA repair mechanisms is most likely defective in this condition?

Explanation

## Correct Answer: A. Nucleotide excision repair The clinical presentation of skin cancer with photosensitive hyperpigmentation worsening on sunlight exposure is pathognomonic for **Xeroderma Pigmentosum (XP)**, a rare autosomal recessive disorder caused by defective **nucleotide excision repair (NER)**. NER is the primary mechanism for removing UV-induced DNA lesions, particularly thymine dimers and 6-4 photoproducts formed by UVB/UVA radiation. In XP, defective NER allows accumulation of unrepaired UV-induced DNA damage in skin cells, leading to (1) severe photosensitivity with acute sunburn-like reactions even after brief sun exposure, (2) progressive hyperpigmentation and hypopigmentation (poikiloderma), and (3) dramatically increased risk of skin cancers (melanoma, basal cell carcinoma, squamous cell carcinoma) by age 10–20 years in Indian patients with high sun exposure. The defect affects genes encoding XPA–XPG proteins essential for NER initiation, lesion recognition, and excision. NER is also critical for removing bulky adducts from carcinogens (e.g., benzo[a]pyrene), making it the most versatile DNA repair pathway for environmental mutagens. This is the only repair mechanism specifically evolved to handle UV photoproducts, making it the discriminating answer. ## Why the other options are wrong **B. Mismatch repair** — Mismatch repair (MMR) corrects base-pairing errors introduced during DNA replication (e.g., A–C mismatches), not UV-induced lesions. Defects in MMR genes (MLH1, MSH2) cause Lynch syndrome with colorectal and endometrial cancers, not photosensitive skin disease. MMR is irrelevant to sunlight-induced damage. **C. Non-homologous end joining (NHEJ)** — NHEJ repairs double-strand breaks (DSBs) caused by ionizing radiation or replication fork collapse, not UV-induced thymine dimers. Defects in NHEJ proteins (Ku70, DNA-PKcs) cause severe combined immunodeficiency (SCID) or ataxia-telangiectasia, not photosensitive skin cancer. NHEJ does not process UV photoproducts. **D. Base excision repair** — Base excision repair (BER) removes small, non-bulky DNA lesions (oxidative damage, alkylation, deamination) via glycosylase-initiated pathways. BER does not handle bulky UV-induced lesions or thymine dimers. Defects in BER cause Cockayne syndrome (neurodegeneration) or progeria, not XP-like photosensitivity with skin cancer. ## High-Yield Facts - **Xeroderma Pigmentosum (XP)** is caused by defective nucleotide excision repair (NER), leading to photosensitivity, poikiloderma, and 1000-fold increased skin cancer risk. - **NER removes thymine dimers and 6-4 photoproducts** formed by UVB/UVA radiation; it is the only repair pathway that handles bulky UV lesions. - **XP patients in India** present with severe sunburn after minimal sun exposure and develop skin cancers by age 10–20 years; strict photoprotection is the only management. - **NER involves 7 complementation groups (XPA–XPG)** in humans; defects in any XP gene impair the entire NER pathway. - **Mismatch repair** corrects replication errors; **NHEJ** repairs double-strand breaks; **BER** removes small oxidative lesions—none handle UV photoproducts. ## Mnemonics **NER = UV Repair** **N**ucleotide **E**xcision **R**epair = **N**othing **E**lse **R**emoves UV lesions. NER is the exclusive pathway for thymine dimers and 6-4 photoproducts. When you see photosensitivity + skin cancer, think NER defect. **XP = eXcision Problem** **X**eroderma **P**igmentosum = defective e**X**cision of UV lesions. The 'X' in XP stands for the defective excision repair mechanism (NER). Photosensitivity + poikiloderma + early skin cancer = XP. ## NBE Trap NBE may pair "skin cancer" with "mismatch repair" (Lynch syndrome) to trap students who confuse different cancer predisposition syndromes. The key discriminator is **photosensitivity worsening with sunlight**—only NER defects cause this UV-specific phenotype. ## Clinical Pearl In Indian dermatology practice, XP is rare but devastating: affected children develop severe erythema and blistering after 15–30 minutes of sun exposure, followed by progressive hyperpigmentation and multiple skin cancers by adolescence. Early diagnosis via NER assay and strict photoprotection (protective clothing, SPF 50+ sunscreen, UV-blocking windows) are life-saving interventions. _Reference: Robbins Ch. 7 (Genetic Disorders); Harrison Ch. 52 (Photosensitivity Disorders); KD Tripathi Ch. 12 (DNA Repair)_