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Molecular analysis of mutations in DNA polymerase ? in xeroderma pigmentosum-variant patients
journal contribution
posted on 2023-06-07, 13:56 authored by Bernard C Broughton, Agnes Cordonnier, Wim J Kleijer, Nicolaas G J Jaspers, Heather Fawcett, Heather Raams, Victor H. Garritsen, Anne Stary, Marie-Francoise Avril, Francois Boudsocq, Chikahide Masutani, Fumio Hanaoka, Robert P Fuchs, Alain Sarasin, Alan LehmannAlan LehmannXeroderma pigmentosum variant (XP-V) cells are deficient in their ability to synthesize intact daughter DNA strands after UV irradiation. This deficiency results from mutations in the gene encoding DNA polymerase eta, which is required for effecting translesion synthesis (TLS) past UV photoproducts. We have developed a simple cellular procedure to identify XP-V cell strains, and have subsequently analyzed the mutations in 21 patients with XP-V. The 16 mutations that we have identified fall into three categories. Many of them result in severe truncations of the protein and are effectively null alleles. However, we have also identified five missense mutations located in the conserved catalytic domain of the protein. Extracts of cells falling into these two categories are defective in the ability to carry out TLS past sites of DNA damage. Three mutations cause truncations at the C terminus such that the catalytic domains are intact, and extracts from these cells are able to carry out TLS. From our previous work, however, we anticipate that protein in these cells will not be localized in the nucleus nor will it be relocalized into replication foci during DNA replication. The spectrum of both missense and truncating mutations is markedly skewed toward the N-terminal half of the protein. Two of the missense mutations are predicted to affect the interaction with DNA, the others are likely to disrupt the three-dimensional structure of the protein. There is a wide variability in clinical features among patients, which is not obviously related to the site or type of mutation.
History
Publication status
- Published
Journal
Proceedings of the National Academy of Sciences of the United States of AmericaISSN
1091-6490Publisher
National Academy of SciencesExternal DOI
Issue
2Volume
99Page range
815-820Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Notes
GDSC11Full text available
- No
Peer reviewed?
- Yes