XPD

XPD, also known as XP-D, refers to a DNA helicase that is a key component of the transcription factor IIH (TFIIH) complex. In humans, XPD is encoded by the ERCC2 gene. Its primary roles are in nucleotide excision repair (NER), where it helps unwind DNA around bulky lesions such as ultraviolet-induced pyrimidine dimers, and in transcription initiation as part of TFIIH. XPD works together with other TFIIH subunits, including XPB, and relies on ATP hydrolysis to drive DNA unwinding.

Protein and molecular features are characteristic of a 5'-3' helicase belonging to superfamily II. XPD contains an iron-sulfur cluster that is important for structural integrity and helicase activity. Its proper function is coordinated with interacting factors such as XPA and other TFIIH components, enabling coordinated repair of DNA damage and transcriptional initiation.

Genetic and clinical significance are most prominent in the XP-D complementation group. Mutations in ERCC2/XPD cause xeroderma pigmentosum group D, an autosomal recessive disorder marked by extreme sensitivity to sunlight and a high risk of skin cancers. Phenotypes can vary widely; some individuals present with the classical XP-D features, while others exhibit syndromic forms such as trichothiodystrophy (TTD) with hair abnormalities and developmental issues. Less commonly, XP-D–related cases may display features overlapping with other NER-related disorders.

Diagnosis typically involves genetic testing to identify ERCC2/XPD variants, supported by clinical assessment and family history. Management emphasizes sun protection, regular dermatologic surveillance for skin cancers, and multidisciplinary care for associated features. There is no cure for XP-D; treatment is supportive and focuses on minimizing DNA damage and monitoring health risks. Research continues into the precise functions of XPD within TFIIH and potential targeted therapies for NER-related disorders.

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