Efficiency of the DNA repair and polymorphisms of the XRCC1,XRCC3 and XRCC4 DNA repair genes in systemic lupus erythematosus

Abstract

Impaired DNA repair efficiency in systemic lupus erythematosus (SLE) patients has been reported in some studies, mainly regarding the repair of oxidative damage, but little is known about repair kinetics towards primarily single-stranded DNA breaks. In the present study, we aimed to investigate: (a) the efficiency of SLE peripheral blood leucocytes in repairing DNA damage induced by ionizing radiation and (b) the association of DNA repair gene (XRCC1 Arg399Gln, XRCC3 Thr241Met and XRCC4 Ile401Thr) polymorphisms in SLE patients, considering the whole group, or stratified sub-groups according to clinical and laboratory features. A total of 163 SLE patients and 125 healthy controls were studied. The kinetics of DNA strand break repair was evaluated by the comet assay, and genotyping for DNA repair genes was performed by PCR-RFLP. Compared with controls, SLE leucocytes exhibited decreased efficiency of DNA repair evaluated at 30 min following irradiation. A significant association with DNA repair gene polymorphisms was not observed for the whole group of SLE patients; however, the XRCC1Arg399Gln polymorphism was associated with the presence of anti-dsDNA antibody. The concomitance of two DNA repair polymorphic sites was associated with the presence of neuropsychiatric manifestations and antiphospholipid antibody syndrome. Taken together, these results indicated that SLE leucocytes repair less efficiently the radiation-induced DNA damage, and DNA repair polymorphic sites may predispose to the development of particular clinical and laboratory features.

Keywords

DNA repair polymorphisms SLE XRCC1 XRCC3 XRCC4

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References

1 Tan EM Cohen AS Fries JF . The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

2 Tsao BP . The genetics of human systemic lupus erythematosus. Trends Immunol 2003; 24: 595–602.

3 Stollar BD . Antibodies to DNA. CRC Crit Rev Biochem 1986; 20: 1–36.

4 Blount S Griffiths H Emery P Lunec J . Reactive oxygen species modify human DNA, eliciting a more discriminating antigen for the diagnosis of systemic lupus erythematosus. Clin Exp Immunol 1990; 81: 384–389.

5 Cooke MS Mistry N Wood C Herbert KE Lunec J . Immunogenicity of DNA damaged by reactive oxygen species – implications for anti-DNA antibodies in lupus. Free Radic Biol Med 1997; 22: 151–159.

6 Thomas TJ Messner RP . Effects of lupus-inducing drugs on the B to Z transition of synthetic DNA. Arthritis Rheum 1986; 29: 638–645.

7 Masson M Niedergang C Schreiber V Muller S Menissier-de Murcia J de Murcia G . XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol 1998; 18: 3563–3571.

8 Caldecott KW Aoufouchi S Johnson P Shall S . XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular 'nick-sensor' in vitro. Nucleic Acids Res 1996; 24: 4387–4394.

9 Thompson LH West MG . XRCC1 keeps DNA from getting stranded. Mutat Res 2000; 459: 1–18.

10.

10 Shen MR Jones IM Mohrenweiser H . Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 1998; 58: 604–608.

11.

11 Abdel-Rahman SZ El-Zein RA . The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett 2000; 159: 63–71.

12.

12 Aka P Mateuca R Buchet JP Thierens H Kirsch-Volders M . Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations. Mutat Res 2004; 556: 169–181.

13.

13 Schild D Lio YC Collins DW Tsomondo T Chen DJ . Evidence for simultaneous protein interactions between human Rad51 paralogs. J Biol Chem 2000; 275: 16443–16449.

14.

14 Araujo FD Pierce AJ Stark JM Jasin M . Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks. Oncogene 2002; 21: 4176–4180.

15.

15 Matullo G Palli D Peluso M . XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis 2001; 22: 1437–1445.

16.

16 Lees-Miller SP Meek K . Repair of DNA double strand breaks by non-homologous end joining. Biochimie 2003; 85: 1161–1173.

17.

17 Ford BN Ruttan CC Kyle VL Brackley ME Glickman BW . Identification of single nucleotide polymorphisms in human DNA repair genes. Carcinogenesis 2000; 21: 1977–1981.

18.

18 Benke PJ Belmar P . Phytohemagglutinin-stimulated lymphocytes from patients with systemic lupus erythematosus demonstrate DNA damage. Metabolism 1991; 40: 1037–1042.

19.

19 Bashir S Harris G Denman MA Blake DR Winyard PG . Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune diseases. Ann Rheum Dis 1993; 52: 659–666.

20.

20 McConnell JR Crockard AD Cairns AP Bell AL . Neutrophils from systemic lupus erythematosus patients demonstrate increased nuclear DNA damage. Clin Exp Rheumatol 2002; 20: 653–660.

21.

21 McCurdy D Tai LQ Frias S Wang Z . Delayed repair of DNA damage by ionizing radiation in cells from patients with juvenile systemic lupus erythematosus and rheumatoid arthritis. Radiat Res 1997; 147: 48–54.

22.

22 Mandel M Gurevich M Pauzner R Kaminski N Achiron A . Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus. Clin Exp Immunol 2004; 138: 164–170.

23.

23 Pereira E Tamia-Ferreira MC Cardoso RS . Immunosuppressive therapy modulates T lymphocyte gene expression in patients with systemic lupus erythematosus. Immunology 2004; 113: 99–105.

24.

24 Pastinen T Ge B Hudson TJ . Influence of human genome polymorphism on gene expression. Hum Mol Genet 2006; 15: R9–R16.

25.

25 Singh NP McCoy MT Tice RR Schneider EL . A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 1988; 175: 184–191.

26.

26 Manoharan K Banerjee MR . beta-Carotene reduces sister chromatid exchanges induced by chemical carcinogens in mouse mammary cells in organ culture. Cell Biol Int Rep 1985; 9: 783–789.

27.

27 Waters MD Brady AL Stack HF Brockman HE . Antimutagenicity profiles for some model compounds. Mutat Res 1990; 238: 57–85.

28.

28 Relton CL Daniel CP Hammal DM Parker L Janet Tawn E Burn J . DNA repair gene polymorphisms, pre-natal factors and the frequency of somatic mutations in the glycophorin-A gene among healthy newborns. Mutat Res 2004; 545: 49–57.

29.

29 Evans MD Cooke MS Akil M Samanta A Lunec J . Aberrant processing of oxidative DNA damage in systemic lupus erythematosus. Biochem Biophys Res Commun 2000; 273: 894–898.

30.

30 Grob M Wyss M Spycher MA . Histopathologic and ultrastructural study of lupus-like skin lesions in a patient with Bloom syndrome. J Cutan Pathol 1998; 25: 275–278.

31.

31 Makker SP Widstrom R Huang J . Membranous nephropathy, interstitial nephritis, and Fanconi syndrome – glomerular antigen. Pediatr Nephrol 1996; 10: 7–13.

32.

32 Griswold WR Krous HF Reznik V . The syndrome of autoimmune interstitial nephritis and membranous nephropathy. Pediatr Nephrol 1997; 11: 699–702.

33.

33 Kasatkina EP Shilin DE Rosenbloom AL . Effects of low level radiation from the Chernobyl accident in a population with iodine deficiency. Eur J Pediatr 1997; 156: 916–920.

34.

34 Sakaguchi N Miyai K Sakaguchi S . Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells. J Immunol 1994; 152: 2586–2595.

35.

35 Silva LM Garcia AB Donadi EA . Increased lymphocyte death by neglect-apoptosis is associated with lymphopenia and autoantibodies in lupus patients presenting with neuropsychiatric manifestations. J Neurol 2002; 249: 1048–1054.

36.

36 Hur JW Sung YK Shin HD Park BL Cheong HS Bae SC . Poly(ADP-ribose) polymerase (PARP) polymorphisms associated with nephritis and arthritis in systemic lupus erythematosus. Rheumatology (Oxford) 2006; 45: 711–717.

37.

37 Duarte MC Colombo J Rossit AR . Polymorphisms of DNA repair genes XRCC1 and XRCC3, interaction with environmental exposure and risk of chronic gastritis and gastric cancer. World J Gastroenterol 2005; 11: 6593–6600.

38.

38 Dufloth RM Costa S Schmitt F Zeferino LC . DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas, Brazil. Genet Mol Res 2005; 4: 771–782.

39.

39 Marczynski B Czuppon AB Marek W Reichel G Baur X . Increased incidence of DNA double-strand breaks and anti-ds DNA antibodies in blood of workers occupationally exposed to asbestos. Hum Exp Toxicol 1994; 13: 3–9.

40.

40 Waris G Alam K . Immunogenicity of superoxide radical modified-DNA: studies on induced antibodies and SLE anti-DNA autoantibodies. Life Sci 2004; 75: 2633–2642.

41.

41 Ballok DA . Neuroimmunopathology in a murine model of neuropsychiatric lupus. Brain Res Rev 2007; 54: 67–79.

42.

42 Rauch J Subang R D'Agnillo P Koh JS Levine JS . Apoptosis and the antiphospholipid syndrome. J Autoimmun 2000; 15: 231–235.