Nucleotide excision repair (NER) corrects bulky DNA adducts caused by UV radiation (cyclobutane pyrimidine dimers). Which genetic disorder results from defective NER, presenting with extreme photosensitivity, skin cancer, and neurological degeneration?

• A Xeroderma pigmentosum (XP genes encoding NER endonucleases) ✓
• B Ataxia-telangiectasia (defective ATM kinase)
• C HNPCC/Lynch syndrome (defective mismatch repair)
• D Fanconi anaemia (defective interstrand crosslink repair)

Explanation

Xeroderma pigmentosum results from mutations in XPA–XPG genes encoding proteins of the NER pathway, which recognises and excises bulky adducts (UV-induced cyclobutane pyrimidine dimers and 6-4 photoproducts). Patients have extreme UV sensitivity, freckling, keratoses, and skin cancers (melanoma, SCC, BCC) at a >1000-fold elevated rate; neurological degeneration results from failure to repair oxidative DNA adducts in post-mitotic neurons. ATM deficiency (ataxia-telangiectasia) is a DSB sensor defect. Lynch syndrome involves MSH2/MLH1 mismatch repair. Fanconi anaemia involves FANC proteins for interstrand crosslink repair.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.