Increased Apoptosis, P53 Up-regulation, and Cerebellar Neuronal Degeneration in Repair-deficient Cockayne Syndrome Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Jan 19

PMID 17229834

Citations 51

Authors

R R Laposa

E J Huang

J E Cleaver

Affiliations

Soon will be listed here.

Abstract

Cockayne syndrome (CS) is a rare recessive childhood-onset neurodegenerative disease, characterized by a deficiency in the DNA repair pathway of transcription-coupled nucleotide excision repair. Mice with a targeted deletion of the CSB gene (Csb-/-) exhibit a much milder ataxic phenotype than human patients. Csb-/- mice that are also deficient in global genomic repair [Csb-/-/xeroderma pigmentosum C (Xpc)-/-] are more profoundly affected, exhibiting whole-body wasting, ataxia, and neural loss by postnatal day 21. Cerebellar granule cells demonstrated high TUNEL staining indicative of apoptosis. Purkinje cells, identified by the marker calbindin, were severely depleted and, although not TUNEL-positive, displayed strong immunoreactivity for p53, indicating cellular stress. A subset of animals heterozygous for Csb and Xpc deficiencies was more mildly affected, demonstrating ataxia and Purkinje cell loss at 3 months of age. Mouse, Csb-/-, and Xpc-/- embryonic fibroblasts each exhibited increased sensitivity to UV light, which generates bulky DNA damage that is a substrate for excision repair. Whereas Csb-/-/Xpc-/- fibroblasts were more UV-sensitive than either single knockout, double-heterozygote fibroblasts had normal UV sensitivity. Csb-/- mice crossed with a strain defective in base excision repair (Ogg1) demonstrated no enhanced neurodegenerative phenotype. Complete deficiency in nucleotide excision repair therefore renders the brain profoundly sensitive to neurodegeneration in specific cell types of the cerebellum, possibly because of unrepaired endogenous DNA damage that is a substrate for nucleotide but not base excision repair.

Citing Articles

Proteins Associated with Neurodegenerative Diseases: Link to DNA Repair.

Khodyreva S, Dyrkheeva N, Lavrik O Biomedicines. 2025; 12(12.

PMID: 39767715 PMC: 11673744. DOI: 10.3390/biomedicines12122808.

Perspectives in the investigation of Cockayne syndrome group B neurological disease: the utility of patient-derived brain organoid models.

Wang X, Zheng R, Dukhinova M, Wang L, Shen Y, Lin Z J Zhejiang Univ Sci B. 2024; 25(10):878-889.

PMID: 39420523 PMC: 11494160. DOI: 10.1631/jzus.B2300712.

Cockayne Syndrome Linked to Elevated R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation.

Zhang X, Xu J, Hu J, Zhang S, Hao Y, Zhang D Nat Commun. 2024; 15(1):6031.

PMID: 39019869 PMC: 11255242. DOI: 10.1038/s41467-024-50298-w.

The ARK2N-CK2 complex initiates transcription-coupled repair through enhancing the interaction of CSB with lesion-stalled RNAPII.

Luo Y, Li J, Li X, Lin H, Mao Z, Xu Z Proc Natl Acad Sci U S A. 2024; 121(24):e2404383121.

PMID: 38843184 PMC: 11181095. DOI: 10.1073/pnas.2404383121.

Nucleotide excision repair in Human cell lines lacking both XPC and CSB proteins.

Lindsey-Boltz L, Yang Y, Kose C, Deger N, Eynullazada K, Kawara H Nucleic Acids Res. 2023; 51(12):6238-6245.

PMID: 37144462 PMC: 10325923. DOI: 10.1093/nar/gkad334.

References

Cline S, Riggins J, Tornaletti S, Marnett L, Hanawalt P . Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II. Proc Natl Acad Sci U S A. 2004; 101(19):7275-80. PMC: 409909. DOI: 10.1073/pnas.0402252101. View

Lee Y, Barnes D, Lindahl T, McKinnon P . Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 2000; 14(20):2576-80. PMC: 316986. DOI: 10.1101/gad.837100. View

Kuraoka I, Robins P, Masutani C, Hanaoka F, Gasparutto D, Cadet J . Oxygen free radical damage to DNA. Translesion synthesis by human DNA polymerase eta and resistance to exonuclease action at cyclopurine deoxynucleoside residues. J Biol Chem. 2001; 276(52):49283-8. DOI: 10.1074/jbc.M107779200. View

Florez-McClure M, Linseman D, Chu C, Barker P, Bouchard R, Le S . The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci. 2004; 24(19):4498-509. PMC: 1876689. DOI: 10.1523/JNEUROSCI.5744-03.2004. View

Murai M, Enokido Y, Inamura N, Yoshino M, Nakatsu Y, van der Horst G . Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne syndrome Group B DNA repair genes. Proc Natl Acad Sci U S A. 2001; 98(23):13379-84. PMC: 60879. DOI: 10.1073/pnas.231329598. View

Dolle M, Busuttil R, Garcia A, Wijnhoven S, van Drunen E, Niedernhofer L . Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res. 2006; 596(1-2):22-35. DOI: 10.1016/j.mrfmmm.2005.11.008. View

Tuo J, Jaruga P, Rodriguez H, Bohr V, Dizdaroglu M . Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress. FASEB J. 2003; 17(6):668-74. DOI: 10.1096/fj.02-0851com. View

Herrup K, Neve R, Ackerman S, Copani A . Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci. 2004; 24(42):9232-9. PMC: 6730083. DOI: 10.1523/JNEUROSCI.3347-04.2004. View

Kohji T, Hayashi M, Shioda K, Minagawa M, Morimatsu Y, Tamagawa K . Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci Lett. 1998; 243(1-3):133-6. DOI: 10.1016/s0304-3940(98)00109-8. View

10.

van der Horst G, van Steeg H, Berg R, van Gool A, de Wit J, Weeda G . Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell. 1997; 89(3):425-35. DOI: 10.1016/s0092-8674(00)80223-8. View

11.

Check E . Retracted papers damage work on DNA repair. Nature. 2005; 435(7045):1015. DOI: 10.1038/4351015a. View

12.

Ide H . DNA substrates containing defined oxidative base lesions and their application to study substrate specificities of base excision repair enzymes. Prog Nucleic Acid Res Mol Biol. 2001; 68:207-21. DOI: 10.1016/s0079-6603(01)68101-7. View

13.

Wood R, Mitchell M, Sgouros J, Lindahl T . Human DNA repair genes. Science. 2001; 291(5507):1284-9. DOI: 10.1126/science.1056154. View

14.

Fonnum F, Lock E . The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells. J Neurochem. 2004; 88(3):513-31. DOI: 10.1046/j.1471-4159.2003.02211.x. View

15.

de Boer J, Andressoo J, de Wit J, Huijmans J, Beems R, van Steeg H . Premature aging in mice deficient in DNA repair and transcription. Science. 2002; 296(5571):1276-9. DOI: 10.1126/science.1070174. View

16.

Nouspikel T, HANAWALT P . Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol Cell Biol. 2000; 20(5):1562-70. PMC: 85340. DOI: 10.1128/MCB.20.5.1562-1570.2000. View

17.

Waard H, de Wit J, Gorgels T, van den Aardweg G, Andressoo J, Vermeij M . Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA Repair (Amst). 2003; 2(1):13-25. DOI: 10.1016/s1568-7864(02)00188-x. View

18.

Cooper P, Nouspikel T, Clarkson S, Leadon S . Defective transcription-coupled repair of oxidative base damage in Cockayne syndrome patients from XP group G. Science. 1997; 275(5302):990-3. DOI: 10.1126/science.275.5302.990. View

19.

Voigt J, Van Houten B, Sancar A, Topal M . Repair of O6-methylguanine by ABC excinuclease of Escherichia coli in vitro. J Biol Chem. 1989; 264(9):5172-6. View

20.

McMurray C . To die or not to die: DNA repair in neurons. Mutat Res. 2005; 577(1-2):260-74. DOI: 10.1016/j.mrfmmm.2005.03.006. View