Xeroderma Pigmentosum and the DNA Damage Response to Ultraviolet Light

Abstract

The DNA damage response restores DNA integrity and protects against genomic instability that can lead to cancer. The human disease xeroderma pigmentosum (XP) is a prime example of disorders affecting several stages of the damage response: nucleotide excision repair (NER), transcription, and DNA replication. NER repairs damage in the form of large modifications to nucleotides such as pyrimidine dimers from UV light, DNA adducts from carcinogenic chemicals, and some oxidative products. NER replaces the damage with a 27–29 nucleotide patch by a combination of damage recognition, verification, DNA unwinding, 3′ and 5′ cleavage, and DNA replication. Two main pathways can be distinguished: (1) global repair in which initial damage recognition occurs through dedicated proteins XPC/HR23B and XPE (DDB1/DDB2), and (2) transcription-coupled repair (TCR) in which damage recognition occurs as a result of RNA pol II arrest. Two proteins dedicated to TCR, CSA and CSB, are required for RNA pol II ubiquitination and are mutated in the sun-sensitive neurodegenerative disease Cockayne syndrome (CS). Overlap of NER with repair of oxidative damage may be responsible for the neural degeneration in CS and some XP groups. DNA damage blocks the replicative polymerases alpha, delta, and epsilon and is replicated by damage-specific polymerases, mainly Pol eta and Pol iota of the class Y low fidelity polymerases. NER is vitally important for protection against solar-induced damage that can lead to immunosuppression and skin cancer, including melanoma. Polymorphisms in NER genes have been associated with a range of other human cancers.