The cerebro-oculo-facio-skeletal syndrome point mutation F231L in the ERCC1 DNA repair protein causes dissociation of the ERCC1-XPF complex

Maryam Faridounnia, Hans Wienk, Lidija Kovačič, Gert E. Folkers, Nicolaas G.J. Jaspers, Robert Kaptein, Jan H.J. Hoeijmakers, Rolf Boelens

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

The ERCC1-XPF heterodimer, a structure-specific DNA endonuclease, is best known for its function in the nucleotide excision repair (NER) pathway. The ERCC1 point mutation F231L, located at the hydrophobic interaction interface of ERCC1 (excision repair cross-complementation group 1) and XPF (xeroderma pigmentosum complementation group F), leads to severe NER pathway deficiencies. Here, we analyze biophysical properties and report the NMR structure of the complex of the C-terminal tandem helix-hairpin-helix domains of ERCC1-XPF that contains this mutation. The structures of wild type and the F231L mutant are very similar. The F231L mutation results in only a small disturbance of the ERCC1-XPF interface, where, in contrast to Phe231, Leu231 lacks interactions stabilizing the ERCC1-XPF complex. One of the two anchor points is severely distorted, and this results in a more dynamic complex, causing reduced stability and an increased dissociation rate of the mutant complex as compared with wild type. These data provide a biophysical explanation for the severe NER deficiencies caused by this mutation.

Original languageEnglish
Pages (from-to)20541-20555
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number33
DOIs
Publication statusPublished - 14 Aug 2015
Externally publishedYes

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