Xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a rare, inherited genetic disorder characterized by an extreme sensitivity to ultraviolet (UV) light, leading to severe skin damage, early onset of skin cancer, and a host of other symptoms such as neurological deficits in some cases. XP is primarily caused by defects in the DNA repair mechanisms that protect the skin from UV-induced damage, particularly defects in nucleotide excision repair (NER), which is responsible for repairing UV-induced DNA lesions.

There are two main sub-pathways within NER: global genomic repair (GGR) and transcription-coupled repair (TCR). Both are crucial for maintaining DNA integrity after UV exposure, and defects in the enzymes involved in these pathways contribute to the clinical manifestations of XP.

1. Global Genomic Repair (GGR)

Global genomic repair (GGR) is a DNA repair pathway that removes a broad range of UV-induced DNA lesions, such as pyrimidine dimers (e.g., thymine dimers), from the entire genome. The GGR pathway is responsible for detecting and repairing DNA damage throughout the genome, regardless of whether the DNA is actively being transcribed.

Defective Enzymes in GGR:

The key enzymes involved in GGR are part of the nucleotide excision repair (NER) machinery. In XP, defects in the following NER proteins can lead to GGR dysfunction:

• XPC (Xeroderma Pigmentosum group C): The XPC protein, in association with its co-factor, hHR23B, recognizes UV-induced DNA damage in the genome. When the DNA is damaged, XPC binds to the lesion and recruits other NER proteins to excise the damaged DNA segment. Mutations in the XPC gene result in defective GGR and contribute to the development of XP.

• XPE (Xeroderma Pigmentosum group E): The XPE protein is involved in damage recognition, and in some cases, it forms a complex with DDB1 and DDB2, which are part of the damage recognition complex. Mutations in XPE impair the recognition of UV-induced lesions, preventing proper GGR function.

• XPA (Xeroderma Pigmentosum group A): XPA plays a role in the stabilization of the NER complex and the incision of the DNA strand containing the damage. Mutations in XPA result in a defective ability to initiate repair at the damaged site.

• Other proteins involved in GGR: Additional proteins such as ERCC1, ERCC4 (XPF), and XPG participate in the later stages of NER, which involve the excision of the damaged DNA strand and the repair synthesis of the undamaged strand. Mutations in ERCC1, XPF, or XPG can impair the incision and repair processes, leading to XP.

2. Transcription-Coupled Repair (TCR)

Transcription-coupled repair (TCR) is a sub-pathway of NER that specifically repairs DNA damage in the transcribed strand of active genes. This repair pathway is vital for maintaining the integrity of actively transcribed genes, as the transcription machinery can stall when encountering DNA lesions like pyrimidine dimers. In TCR, the transcription machinery itself acts as a signal for the repair process.

Defective Enzymes in TCR

TCR involves many of the same proteins as GGR, but the process is particularly influenced by the interaction of DNA damage with the transcription machinery.

• RNA Polymerase II (RNAP II): The transcription machinery, specifically RNA polymerase II, plays a critical role in TCR by stalling when it encounters a lesion on the DNA template strand. This stalling acts as a signal to recruit repair proteins to the damage site.

• CSB (Cockayne Syndrome B): The CSB protein is crucial for TCR. It recognizes transcription-coupled DNA damage and helps to recruit other repair proteins to the site of damage. Mutations in CSB are associated with Cockayne Syndrome (CS), a disease that shares features with XP, such as sensitivity to UV radiation but with additional neurological symptoms. The CSB protein works with CSA (Cockayne Syndrome A) to initiate the repair process in TCR.

• XPG (Xeroderma Pigmentosum group G): Although XPG is involved in both GGR and TCR, its role in TCR is particularly important. XPG helps to cleave the damaged strand during repair and is recruited to the damaged transcription bubble, facilitating repair in actively transcribed regions.

Defects in TCR and Their Contribution to XP

In XP, **TCR defects are more evident in some XP subtypes, particularly in XP patients with mutations in the CSA or CSB proteins. TCR deficiency leads to inefficient repair of transcriptionally active genes, which can contribute to the neurological symptoms seen in some XP patients, as these areas of the genome are particularly vulnerable to UV-induced mutations. However, in most XP subtypes, defects in TCR are secondary to the primary defects in global genomic repair.

Clinical Manifestations of Xeroderma Pigmentosum

The defects in GGR and TCR result in the hallmark symptoms of XP, which include:

• Extreme sensitivity to UV light, leading to severe sunburns even after minimal sun exposure.
• Premature skin aging and the development of freckles, dry skin, and actinic keratosis.
• Increased risk of skin cancers, such as basal cell carcinoma, squamous cell carcinoma, and melanoma, often at a very young age.
• Neurological complications (in some subtypes), including hearing loss, developmental delays, and motor abnormalities, which are thought to result from the failure to repair UV-induced damage in the nervous system.

Xeroderma pigmentosum is caused by mutations in genes involved in the nucleotide excision repair pathways, which are critical for repairing UV-induced DNA damage. Defects in global genomic repair (GGR) proteins like XPC, XPA, and XPE and transcription-coupled repair (TCR) proteins like CSB and XPG lead to a failure to repair UV-induced lesions, causing the clinical features of XP. The defective repair of both actively transcribed and non-transcribed regions of the genome results in increased DNA damage, particularly after UV exposure, and contributes to the severe symptoms observed in affected individuals.