Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair (NER). XP complementation group A (XPA) protein functions as a damage recognition scaffold. A patient in complementation group D has a mutation in the XPD/ERCC2 gene, which encodes a helicase subunit of the TFIIH complex. This mutation causes XP but also features of Cockayne syndrome (neurodegeneration). Why does XPD mutation affect transcription-coupled NER more severely than global genome NER?

• A TFIIH is required only for transcription-coupled NER, not global genome NER
• B XPD is required for RNA polymerase II phosphorylation at Ser5 of the CTD, directly linking repair to transcription initiation
• C XPD helicase activity unwinds DNA at stalled RNA polymerase II complexes, and mutations reduce the coupling efficiency to transcription machinery ✓
• D XPD contains a transcription activation domain that recruits CSB protein specifically in transcription-coupled repair

Explanation

TFIIH is a multi-subunit complex required for both nucleotide excision repair (NER) and RNA polymerase II transcription initiation. In transcription-coupled NER (TC-NER), TFIIH is recruited to stalled RNA Pol II at a lesion site by CSB and CSA proteins. XPD (ERCC2) is the 5'-to-3' helicase subunit of TFIIH that unwinds DNA around the lesion. Certain XPD mutations impair the coupling of TFIIH recruitment to stalled RNA Pol II (reduced interaction efficiency or altered helicase processivity in the transcriptionally active chromatin context), leading to TC-NER deficiency and transcription block on actively transcribed genes, manifesting as neurodegeneration (Cockayne syndrome features). Global genome NER uses XPC for damage recognition and is less sensitive to the same XPD mutation. This explains XP-D's mixed XP/CS phenotype.

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

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Written and medically reviewed by the StethoPrep medical team.