3.6 XP-A

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Xeroderma pigmentosum group A complementing gene (XP-A), codes for a nuclear protein that plays a critical role in nucleotide excision repair (1).   XP-A is considered a caretaker gene because of its function in maintaining the integrity of the genome. Mutations in XP-A, as outlined later in this section, result in an increase in tumorigenic mutations.

 

The XP-A Gene

XP-A is located on 9q34.1 in humans (2) and encodes a 273 amino acid protein containing six exons (3). Exon I encodes the nuclear localization signal (NLS) (4).  Exon II encodes what is known as the “E cluster," which is important for binding to a nucleotide excision repair factor, ERCC1 (5). Exon III contains a zinc-finger domain (2), which is part of a DNA binding domain that expands into exon IV and V (3).  Exon VI is important for binding of TFIIH, a transcription factor which also has nucleotide repair characteristics (6).

 

Normal Function

XP-A recognizes and binds to damaged DNA (7) and directly recruits the nucleotide excision repair complex to the site (5). Recognition is achieved through the protein's specificity to sharply angles in the DNA helix, which characterize specific aberrant DNA lesions (7).

 

When Things Go Wrong

Mutations in XP-A result in a defective repair mechanism.  Defective XP-A leads to the development of a rare autosomal recessive disease, Xeroderma Pigmentosum (XP) (2).  This disease is characterized by hypersensitivity to sunlight and high incidence of skin cancer due to defective DNA repair mechanisms.  In more severe cases, central nervous system disorders may also develop (3).  There are eight complementation groups of this disease (Table 1), and XP-A complements patients in group A.  Genes identified in seven of the eight groups, specifically XP-A to XP-G, all play a role in the DNA excision repair mechanism (8).   A nice, quick animation which depicts the general idea of the DNA nucleotide excision repair mechanism can be found here


Table 3.6.1. Characteristics of the eight XP complementation groups. 

Group

Gene

Proportion of XP linked to Mutations of this gene

Protein function

Defective pathway

A

XPA

25%

Damage verification

NER

B

ERCC3

Rare

Helicase

NER

C

XPC

25%

Damage recognition

NER (GGR)

D

ERCC2

15%

Helicase

NER

E

DDB2

Rare

Damage recognition

NER (GGR)

F

ERCC4

6%

Nuclease

NER

G

ERCC5

6%

Nuclease

NER

Variant

POLH

21%

Polymerase

TLS

GGR: global genome repair sub-pathway, TLS: translesion synthesis. Adapted from Lehmann et al. (9) and Pagon et al. (10).

 

The location of the mutation in XP-A correlates to the severity of the disease in group A patients. Mutation in XP-A usually occurs in the DNA binding region of the protein in a homozygous fashion.  In milder cases, the mutation is usually elsewhere (3).  This suggests that a mutation outside of the DNA binding domain does not completely eliminate XP-A function, as is seen in milder cases of XP (3).  The most common mutation observed in patients with XP (group A) is in a splice acceptor site of intron III, resulting in the missplicing of the gene (8).  Other mutations include transitions, transversions, deletions, and insertion of DNA or amino acid sequence, which potentially causes a frameshift and subsequently results in a missplice, missense, or nonsense mutation (8). Parents of patients diagnosed with Xeroderma Pigmentosum are asymptotic, suggesting a two hit hypothesis in the tumor suppression of XP-A (3).

 

Mutations in XP-A is heritable and is most commonly observed in Japanese and Mediterranean cultures (8).  Mutations in DNA excision repair components, like XP-A, render the cells unable to repair DNA damage due to UV (11). However, many skin tumours also have mutations in genes like p53, which seems to suggest that XP-A mutations may not be enough to cause tumour formation (11).

 


References

  1. Jones, C.J., and Wood, R.D. (1993). Preferential binding of the Xeroderma Pigmentosum group A complementing protein to damaged DNA. Biochemistry 32,12096-12104.
  2. Tanaka, K. et al. (1990). Analysis of a human DNA excision repair gene involved in group A xeroderma pigmentosum and containing a zinc-finger domain. Nature 348, 773-76.
  3. States, J.C., McDuffie, E.R., Myrand, S.P., McDowell, M., and Cleaver, J.E. (1998). Distribution of mutations in the human Xeroderma Pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein. Human mutation 12, 103-113.
  4. Miyamoto, I., Miura, N., Niwa, H., Miyazaki, J., and Tanaka, K. (1992). Mutational analysis of the structure and function of the Xeroderma Pigmentosum group A complementing protein. J. Biol Chem. 267, 12182-12187.
  5. Li, L., Peterson, C.A., Lu, X., and Legerski, R.J. (1995). Mutation in XPA that prevent association with ERCC1 are defective in nucleotide excision repair. Mol. Cell. Biol 15, 1993-1998.
  6. Park, C.H., Mu, D., Reardon, J.T., and Sancar, A. 91995). The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor. J. Biol. Chem. 270, 4895-4902.
  7. PMID: 16491090
  8. Cleaver, J.E., Thompson, L.H., Richardson, A.S., and States, J.C. (1999). A summary of mutations in the UV-sensitive disorders: Xeroderma Pigmentosum, Cockayne Syndrome, and Trichothiodystrophy. Human mutation 14, 9-22.
  9. Lehmann, A., McGibbon, D., and Stefanini, M. (2011). Xeroderma pigmentosum. Orphanet Journal of Rare Diseases6(70):1-6.
  10. Kraemer, K.H., DiGiovanna, J.J. Xeroderma Pigmentosum. 2003 Jun 20 [Updated 2013 Feb 14]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1397/
  11. Van Steeg, and Kraemer, K.H.  (1999).  Xeroderma pigmentosum and the role fo UV-induced skin cancer.  Molecular Medicine Today  5, 86-94.