ERCC2XPD

ERCC2, also known as XPD, is a human gene that encodes a DNA helicase and is a core component of the transcription factor IIH (TFIIH) complex. XPD participates in both transcription initiation and nucleotide excision repair (NER). As part of TFIIH, XPD works with XPB to unwind DNA around bulky lesions, enabling the excision and resynthesis steps that remove UV-induced DNA damage.

XPD’s helicase activity is essential for lesion verification and opening DNA around transcription start sites and repair-prone regions. In NER, XPD coordinates with other TFIIH subunits and repair factors to process helix-distorting lesions, linking DNA repair to transcriptional regulation and chromatin remodeling.

Mutations in ERCC2 cause xeroderma pigmentosum group D (XP-D), an autosomal recessive disorder characterized by extreme sensitivity to sunlight and a high risk of skin cancers; many patients also develop neurological abnormalities or developmental issues depending on mutation severity. Some ERCC2 mutations cause trichothiodystrophy (TTD), a congenital syndrome with brittle hair, ichthyosis, and growth or cognitive problems. Other variants can present with features overlapping Cockayne syndrome. The clinical spectrum reflects residual XPD helicase activity; hypomorphic mutations often yield milder phenotypes, while loss-of-function mutations lead to severe disease.

Diagnosis and management involve genetic testing of ERCC2 to confirm diagnosis, and functional assays such as unscheduled DNA synthesis or helicase assays to support NER defects. Management focuses on sun protection, dermatologic surveillance for skin cancer, and supportive care for neurological or developmental symptoms.

See also: nucleotide excision repair, TFIIH, xeroderma pigmentosum.