Dual role for XPF/ERCC1 ?

ERCC1 exists in a tight complex with XPF [1-3], and free ERCC1 is rapidly degraded [4]. XPF/ERCC1 functions as an endonuclease in mitotic recombination as well as NER [5-8]. Recovery of mice homozygous for altered ERCC1 is far below the Mendelian expectation and those that survive are runted, afflicted with liver, kidney, spleen and skin abnormalities, and have a severely shortened lifespan [7, 9]. As no human disorder has yet been characterised by alteration of ERCC1 function this suggests that human ERCC1 mutants are either not viable or die prior to identification of a DNA repair defect. This phenotype is considerably more severe than that of (completely NER-deficient) XPA mutations, which yield viable (albeit UV-sensitive and cancer-prone) mice and humans [10-12]. Curiously, although both XPF and ERCC1 components are required for both the (recombinational) repair of DNA cross-links and for NER [8], XP-F individuals are characterised by late onset and relatively mild clinical features, compared to the other XP complementation groups (except group E) [13-15]. Furthermore, whereas mutations in the 3' NER endonuclease, XPG [16], result in a complete NER defect [17], mutations in XPF appear to primarily impair 6-4 PP repair, while CPDs are repaired at near normal levels [13, 17-19]. The N-terminal 378 amino acids of XPF are capable of binding and hydrolysing DNA [20]. Of the identified mutations in XPF patients, only one has been observed in this region and this is in a compound heterozygote where the other XPF allele encodes an intact N-terminal domain [15]. As all examined XP-F cells retain at least one normal allele for this region, it has been suggested that the region may be essential for basic cellular function [15].

It therefor seems possible that mutations which compromise the endonuclease activity of XPF/ERCC1 are lethal due to an abrogation of both NER and recombination repair, and further that the XPF/ERCC1 complex contains a second (non-essential) function involved in the recognition of 6-4PPs. According to this model, 6-4 PPs (and possibly other lesions which cause major helical distortion) are initially recognised by a complex of XPA, RPA, XP-E and XP-F/ERCC1, while most other types of DNA damage are first recognised by XPC/HHR23B (see NER figure).

References:

1. Biggerstaff, M., D.E. Szymkowski, and R.D. Wood, Co-correction of the ERCC1, ERCC4 and xeroderma pigmentosum group F DNA repair defects in vitro. EMBO Journal, 1993. 12(9): p. 3685-92.

2. van Vuuren, A.J., et al., Evidence for a repair enzyme complex involving ERCC1 and complementing activities of ERCC4, ERCC11 and xeroderma pigmentosum group F. EMBO Journal, 1993. 12(9): p. 3693-701.

3. Sijbers, A.M., et al., Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell, 1996. 86(5): p. 811-22.

4. Sijbers, A.M., et al., Mutational analysis of the human nucleotide excision repair gene ERCC1. Nucleic Acids Research, 1996. 24(17): p. 3370-80.

5. Murray, D. and E. Rosenberg, The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway. Mutation Research, 1996. 364(3): p. 217-26.

6. Brookman, K.W., et al., ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs. Molecular & Cellular Biology, 1996. 16(11): p. 6553-62.

7. Weeda, G., et al., Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. Curr Biol, 1997. 7(6): p. 427-39.

8. Yagi, T., et al., Sensitivity of group F xeroderma pigmentosum cells to UV and mitomycin C relative to levels of XPF and ERCC1 overexpression. Mutagenesis, 1998. 13(6): p. 595-9.

9. McWhir, J., et al., Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nature Genetics, 1993. 5(3): p. 217-24.

10. de Vries, A., et al., Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature, 1995. 377(6545): p. 169-73.

11. Friedberg, E.C., G.C. Walker, and W. Siede, DNA repair and mutagenesis. 1995, Washington D.C.: ASM Press. 698.

12. Vermeulen, W., et al., Mammalian nucleotide excision repair and syndromes. Biochemical Society Transactions, 1997. 25(1): p. 309-15.

13. Arase, S., et al., A sixth complementation group in xeroderma pigmentosum. Mutat Res, 1979. 59(1): p. 143-6.

14. Moriwaki, S., et al., A case of xeroderma pigmentosum complementation group F with neurological abnormalities. British Journal of Dermatology, 1993. 128(1): p. 91-4.

15. Matsumura, Y., et al., Characterization of molecular defects in xeroderma pigmentosum group F in relation to its clinically mild symptoms. Hum Mol Genet, 1998. 7(6): p. 969-74.

16. O'Donovan, A., et al., XPG endonuclease makes the 3' incision in human DNA nucleotide excision repair. Nature, 1994. 371(6496): p. 432-5.

17. Galloway, A.M., M. Liuzzi, and M.C. Paterson, Metabolic processing of cyclobutyl pyrimidine dimers and (6-4) photoproducts in UV-treated human cells. Evidence for distinct excision-repair pathways. J Biol Chem, 1994. 269(2): p. 974-80.

18. Zelle, B. and P.H. Lohman, Repair of UV-endonuclease-susceptible sites in the 7 complementation groups of xeroderma pigmentosum A through G. Mutat Res, 1979. 62(2): p. 363-8.

19. Zelle, B., F. Berends, and P.H. Lohman, Repair of damage by ultraviolet radiation in xeroderma pigmentosum cell strains of complementation groups E and F. Mutat Res, 1980. 73(1): p. 157-69.

20. McCutchen-Maloney, S.L., et al., Domain mapping of the DNA binding, endonuclease, and ERCC1 binding properties of the human DNA repair protein XPF. Biochemistry, 1999. 38(29): p. 9417-25.