Xeroderma Pigmentosum: A Genetic Disorder Caused by Defects in Nucleotide Excision Repair

Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation and a predisposition to skin cancers. The fundamental cause of XP lies in a defect in the nucleotide excision repair (NER) mechanism, which is responsible for repairing bulky DNA lesions such as UV-induced pyrimidine dimers.

What Is Xeroderma Pigmentosum?

XP patients exhibit:

• Severe sun sensitivity

• Early onset of freckling and pigmentation abnormalities on sun-exposed skin

• High risk of developing skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma)

• In some cases, neurological abnormalities

The disorder results from mutations in genes encoding proteins critical for the NER pathway.

The Role of Nucleotide Excision Repair (NER)

NER is a versatile DNA repair system that removes a wide range of bulky DNA lesions, including:

• UV-induced pyrimidine dimers

• Chemical adducts that distort the DNA helix

NER operates via two sub-pathways:

1. Global Genome NER (GG-NER): Scans the entire genome for DNA damage.

2. Transcription-Coupled NER (TC-NER): Specifically repairs lesions on the transcribed strand of active genes.

Key proteins involved in NER include the products of the XP genes: XPA through XPG. These proteins participate in damage recognition, DNA unwinding, excision of the damaged strand, and repair synthesis.

How Does NER Defect Cause Xeroderma Pigmentosum?

• Mutations in any of the XP genes impair the NER pathway.

• UV-induced DNA damage, especially pyrimidine dimers, accumulates.

• Failure to repair these lesions leads to mutations during DNA replication.

• The accumulation of mutations increases the risk of skin cancers and other symptoms.

Why Other Repair Mechanisms Are Not Responsible

• Base Excision Repair (BER): Repairs small base lesions like oxidized or alkylated bases, not bulky UV-induced lesions.

• Direct Repair Mechanism: Repairs specific lesions like methylated bases but not pyrimidine dimers.

• DNA Replication Mechanism: Errors in replication can cause mutations but are not the primary cause of XP.

Supporting Evidence

• Studies show XP patients have defective NER activity.

• XP gene products (XPA to XPG) have been extensively characterized as NER components.

• Therapeutic strategies targeting NER defects, such as delivery of DNA repair enzymes, improve UV damage repair in XP cells.

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Conclusion

Xeroderma pigmentosum is caused by a defect in the nucleotide excision repair mechanism, which is essential for removing UV-induced DNA lesions such as pyrimidine dimers. This defect leads to the accumulation of DNA damage, resulting in increased mutation rates and a high risk of skin cancers. Therefore, the correct answer is:

(2) Nucleotide excision repair mechanism