Defective DNA Repair and Neurodegenerative Disease
2007; Cell Press; Volume: 130; Issue: 6 Linguagem: Inglês
10.1016/j.cell.2007.08.043
ISSN1097-4172
AutoresUlrich Rass, Ivan Ahel, Stephen C. West,
Tópico(s)Microtubule and mitosis dynamics
ResumoDefects in cellular DNA repair processes have been linked to genome instability, heritable cancers, and premature aging syndromes. Yet defects in some repair processes manifest themselves primarily in neuronal tissues. This review focuses on studies defining the molecular defects associated with several human neurological disorders, particularly ataxia with oculomotor apraxia 1 (AOA1) and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). A picture is emerging to suggest that brain cells, due to their nonproliferative nature, may be particularly prone to the progressive accumulation of unrepaired DNA lesions. Defects in cellular DNA repair processes have been linked to genome instability, heritable cancers, and premature aging syndromes. Yet defects in some repair processes manifest themselves primarily in neuronal tissues. This review focuses on studies defining the molecular defects associated with several human neurological disorders, particularly ataxia with oculomotor apraxia 1 (AOA1) and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). A picture is emerging to suggest that brain cells, due to their nonproliferative nature, may be particularly prone to the progressive accumulation of unrepaired DNA lesions. The link between defective DNA repair and cancer was first established by James E. Cleaver, who recognized that fibroblasts grown in culture from individuals with the hereditary cancer-related disease xeroderma pigmentosum (XP) were defective in the repair of DNA damage induced by UV light (Cleaver, 1968Cleaver J.E. Defective DNA repair replication in xeroderma pigmentosum.Nature. 1968; 218: 652-656Crossref PubMed Scopus (1231) Google Scholar). Most forms of this disease are caused by mutations in genes involved in nucleotide excision repair, a repair pathway that removes UV light-induced DNA lesions. Consequently, XP patients are extremely photosensitive and need to be shielded from sunlight exposure to avoid skin cancer. As Cleaver later stated “XP demonstrated that human cancer was a genetic disease that could be understood in terms of damage and repair to human genes.” His original study of XP also connected DNA repair with neurodegeneration, as it “involved two types of clinical circumstances, both with reduced repair, one with skin cancer, and the other with cancer and neurodegeneration.” About 20% of XP patients suffer from neurological disease characterized by microcephaly (in which the circumference of the head is smaller than average), progressive neurodegeneration involving peripheral neuropathy, loss of reflexes, ataxia, and dementia. The nucleotide excision repair-associated disorders Cockayne syndrome (CS) and trichothiodystrophy (TTD) have overlapping clinical features with XP including neurological defects but are not characterized by an increased susceptibility to cancer (Table 1) (Lehmann, 2003Lehmann A.R. DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy.Biochimie. 2003; 85: 1101-1111Crossref PubMed Scopus (388) Google Scholar).Table 1DNA-Repair Deficiency and NeurodegenerationSyndromeDisease geneNeurological implicationsOtherNucleotide excision repairXeroderma pigmentosum (XP)XPA, XPB, XPD, XPF, XPG, XPVmicrocephaly, progressive neurodegenerationneoplasm of the skin and eyesCockayne syndrome (CS)XPB, XPD, XPG, CSA, CSBmicrocephaly, progressive neurodegenerationdwarfismTrichothiodystrophy (TTD)XPB, XPD, TFB5/TTD-Amicrocephalybrittle hairDNA damage response/DSB repairAtaxia telangiectasia (A-T)ATMataxia, progressive neurodegenerationimmunological implications, lymphoid malignancyAtaxia telangiectasia-like disorder (ATLD)MRE11ataxia, progressive neurodegenerationimmunological implications, lymphoid malignancyNijmegen breakage syndrome (NBS)NBS1microcephalyimmunological implications, lymphoid malignancy, short statureATR-Seckel syndrome (ATR-Seckel)ATRmicrocephalydwarfismPrimary microcephaly 1 (MCPH1)MCPH1/BRIT1microcephalyLIG4 syndromeLIG4microcephalyimmunodeficiency, lymphoid malignancy, developmental and growth delayImmunodeficiency with microcephalyCernunnos/XLFmicrocephalyimmunodeficiency, lymphoid malignancySSB repairAtaxia with oculomotor apraxia 1 (AOA1)Aprataxinataxia, progressive neurodegeneration, oculomotor apraxiahypoalbuminemia, hypercholesterolemiaSpinocerebellar ataxia with axonal neuropathy (SCAN1)Tyrosyl-DNA phosphodiesterase 1ataxia, sensory losshypoalbuminemia, hypercholesterolemiaSyndromes are classified according to the defects in nucleotide excision repair, the DNA-damage response/DNA double-strand break repair, and DNA single-strand break repair. Note that defects in single-strand break repair primarily affect the nervous system. The indicated clinical implications are intended to give an overview and are not comprehensive. Open table in a new tab Syndromes are classified according to the defects in nucleotide excision repair, the DNA-damage response/DNA double-strand break repair, and DNA single-strand break repair. Note that defects in single-strand break repair primarily affect the nervous system. The indicated clinical implications are intended to give an overview and are not comprehensive. Often the occurrence and severity of neurological defects in XP patients correlates with UV sensitivity, suggesting that the nucleotide excision repair defect is directly responsible for neuronal cell death. But as neuronal cells are never exposed to sunlight, the possibility of UV damage is unlikely. Instead, it appears that endogenous damage caused by reactive oxygen species, a consequence of the high rate of oxidative metabolism in the brain, is the underlying cause of neuropathogenic DNA lesions. DNA lesions induced by reactive oxygen species have the potential to block transcription by RNA polymerase II, and their accumulation in repair-defective individuals may cause neuronal cell death, either by progressively depriving the cell of vital transcripts or through apoptosis (Ljungman and Lane, 2004Ljungman M. Lane D.P. Transcription - guarding the genome by sensing DNA damage.Nat. Rev. Cancer. 2004; 4: 727-737Crossref PubMed Scopus (211) Google Scholar). However, a direct correlation between such unrepaired oxidative DNA damage and the neurological implications in XP, CS, and TTD has not been obtained, so this relationship remains open to question and illustrates the difficulty in determining the causative lesion in any of the DNA repair-deficient neurological diseases. Here we discuss the molecular defects associated with several human neurological disorders, particularly ataxia telangiectasia (A-T), ataxia with oculomotor apraxia 1 (AOA1), and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). A-T provides a well-characterized example of the relationships that exist between repair defects and neurodegenerative disease (Table 1). This childhood disease is characterized by progressive impairment of gait and speech, oculomotor apraxia (inability to move the eyes from one object to another), oculocutaneous telangiectasia (dilated blood vessels), cerebellar atrophy, sterility, and radiosensitivity (McKinnon, 2004McKinnon P.J. ATM and ataxia telangiectasia.EMBO Rep. 2004; 5: 772-776Crossref PubMed Scopus (266) Google Scholar). Approximately 10%–15% of A-T patients develop cancer, most frequently acute lymphocytic leukemia and lymphoma. The prognosis for survival is poor, and individuals with this disease usually die in their teens. The pleiotropic clinical manifestations associated with mutations in the ATM gene (which is responsible for A-T) reflect the critical roles played by ATM, a protein kinase required for the cellular response to DNA double-strand breaks (DSBs) (Shiloh, 1997Shiloh Y. Ataxia telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart.Annu. Rev. Genet. 1997; 31: 635-662Crossref PubMed Scopus (417) Google Scholar). In response to DSB formation, ATM kinase is activated and elicits a coordinated damage response that ensures genomic stability by integrating DNA repair with progression through the cell cycle, gene expression, chromatin remodeling, and programmed cell death. Chromosomal DSBs are potentially one of the most dangerous forms of DNA damage that, if left unrepaired, can result in chromosomal aberrations, deletions, or translocations. They can also pose problems during mitosis, as intact chromosomes are required for proper chromosome segregation. Consequently, defects in DSB repair are linked to cell death and tumorigenesis (Burma et al., 2006Burma S. Chen B.P.C. Chen D.J. Role of non-homologous end joining (NHEJ) in maintaining genomic integrity.DNA Repair (Amst.). 2006; 5: 1042-1048Crossref PubMed Scopus (289) Google Scholar). ATM is also involved in immune cell maturation, which proceeds through physiological DSBs and gene rearrangements, as indicated by the immunological implications associated with A-T (Reina-San-Martin et al., 2004Reina-San-Martin B. Chen H.T. Nussenzweig A. Nussenzweig M.C. ATM is required for efficient recombination between immunoglobulin switch regions.J. Exp. Med. 2004; 200: 1103-1110Crossref PubMed Scopus (166) Google Scholar, Xu et al., 1996Xu Y.Z. Ashley T. Brainerd E. Bronson R.T. Meyn M.S. Baltimore D. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma.Genes Dev. 1996; 10: 2411-2422Crossref PubMed Scopus (721) Google Scholar). The pronounced neuropathology of individuals with A-T, however, is more difficult to explain. Why should the nervous system develop normally and then suffer a tissue-specific loss of viability once it has achieved maturity? An important clue to this question was obtained when it was shown that mice lacking the Atm gene lose the ability to induce apoptosis in differentiating neuronal cells, but not in proliferating precursor neuroblasts, in response to DNA damage induced by ionizing radiation (Herzog et al., 1998Herzog K.H. Chong M.J. Kapsetaki M. Morgan J.I. McKinnon P.J. Requirement for ATM in ionizing radiation-induced cell death in the developing central nervous system.Science. 1998; 280: 1089-1091Crossref PubMed Scopus (361) Google Scholar, McConnell et al., 2004McConnell M.J. Kaushal D. Yang A.H. Kingsbury M.A. Rehen S.K. Treuner K. Helton R. Annas E.G. Chun J. Barlow C. Failed clearance of aneuploid embryonic neural progenitor cells leads to excess aneuploidy in the ATM-deficient but not the Trp53-deficient adult cerebral cortex.J. Neurosci. 2004; 24: 8090-8096Crossref PubMed Scopus (52) Google Scholar). These results indicate that ATM may be required for the elimination of damaged neuronal cells during development in order to prevent them from being integrated into a weakened nervous system. There is also some evidence to support the view that ATM deficiency is linked to increased oxidative stress within the cerebellum, the area of the central nervous system most affected in A-T patients (Barlow et al., 1999Barlow C. Dennery P.A. Shigenaga M.K. Smith M.A. Morrow J.D. Roberts L.J. Wynshaw-Boris A. Levine R.L. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.Proc. Natl. Acad. Sci. USA. 1999; 96: 9915-9919Crossref PubMed Scopus (216) Google Scholar, Barzilai et al., 2002Barzilai A. Rotman G. Shiloh Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage.DNA Repair (Amst.). 2002; 1: 3-25Crossref PubMed Scopus (305) Google Scholar, Kamsler et al., 2001Kamsler A. Daily D. Hochman A. Stern N. Shiloh Y. Rotman G. Barzilai A. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from ATM-deficient mice.Cancer Res. 2001; 61: 1849-1854PubMed Google Scholar). These results may indicate that the kinase activity of ATM is required to minimize the progressive accumulation of oxidative DNA lesions. The complex neurological and extraneurological phenotypes seen with A-T are not so unusual. Indeed, they are rather typical of diseases caused by defects in proteins that play important roles in the DNA-damage response and/or are directly involved in the repair of DSBs (Table 1). For example, A-T-like disorder (ATLD) and Nijmegen breakage syndrome (NBS) are very similar to A-T, although NBS is a developmental disorder characterized by microcephaly rather than progressive neurodegeneration. These diseases are caused by hypomorphic mutations in MRE11 and NBS1, respectively. The products of the MRE11 and NBS1 genes associate with RAD50 protein to form the MRE11/RAD50/NBS1 complex that is important for sensing DSBs and activation of ATM kinase activity. This relationship with ATM provides a molecular basis for the phenotypic features shared with A-T. Similarly, ATR-Seckel syndrome, characterized by growth defects, microcephaly, and mental retardation, is caused by a hypomorphic mutation in the ATR gene, which encodes a kinase required for the cellular response to replicative stress. This response involves cell-cycle arrest and replication fork stabilization, which ultimately allows complete progression through S phase (Petermann and Caldecott, 2006Petermann E. Caldecott K.W. Evidence that the ATR/Chk1 pathway maintains normal replication fork progression during unperturbed S phase.Cell Cycle. 2006; 5: 2203-2209Crossref PubMed Scopus (100) Google Scholar). However, although the ATR-Seckel syndrome phenotype suggests an exquisite sensitivity of neuronal cells to DNA damage resulting from replication fork collapse and breakage, the precise determinants for cell-type specificity are unclear. Another microcephaly disorder, primary microcephaly 1 (MCPH1), was recently linked to ATR by observations showing that hypomorphic mutations in the disease gene MCPH1/BRIT1 cause defects in ATR signaling (O'Driscoll et al., 2006O'Driscoll M. Jackson A.P. Jeggo P.A. Microcephalin: a causal link between impaired damage response signalling and microcephaly.Cell Cycle. 2006; 5: 2339-2344Crossref PubMed Scopus (36) Google Scholar). Similarly, microcephaly associated with NBS1 mutation may be related to a downstream function of NBS1 in ATR signaling, one that is quite distinct from its DNA-damage sensor function in ATM signaling (Stiff et al., 2005Stiff T. Reis C. Alderton G.K. Woodbine L. O'Driscoll M. Jeggo P.A. NBS1 is required for ATR-dependent phosphorylation events.EMBO J. 2005; 24: 199-208Crossref PubMed Scopus (153) Google Scholar). Mutations in genes that encode proteins directly involved in DSB repair have also been linked to microcephaly. There are two primary mechanisms of DSB repair in vertebrates—homologous recombination and nonhomologous end joining. DSB repair by nonhomologous end joining is mediated by a number of proteins, including Ku70/Ku80, DNA-PKcs, XLF, and DNA ligase IV/XRCC4 complex, and occurs by a relatively simple end splicing and ligation reaction. Inactivation of nonhomologous end joining in the mouse—through disruption of DNA ligase IV/XRCC4 or XLF (also known as Cernunnos)—can lead to defects in neurogenesis or brain tumours (Barnes et al., 1998Barnes D.E. Stamp G. Rosewell I. Denzel A. Lindahl T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice.Curr. Biol. 1998; 8: 1395-1398Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, Buck et al., 2006Buck D. Malivert L. de Chasseval P. Barraud A. Fondaneche M.C. Sanal O. Plebani A. Stephan J.L. 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Cell. 2001; 8: 1175-1185Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar). For example, the DNA ligase IV-deficient mouse shows massive cell death in the developing nervous system and embryonic lethality. Cell death may be a reflection of the propensity of damaged neuronal cells to induce apoptosis rather than to mature into differentiated neurons. Such a cellular program might be reasonable because cell loss can be compensated for during neurogenesis, but unfortunately, this is not the case with the mature nervous system. DSB repair can also be promoted by RAD51-mediated homologous recombination, which involves interactions between the broken DNA and the sister chromatid (West, 2003West S.C. Molecular views of recombination proteins and their control.Nat. Rev. Mol. Cell Biol. 2003; 4: 435-445Crossref PubMed Scopus (770) Google Scholar). 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This analysis uncovered a new link with neurodegeneration, as BRCA2 inactivation resulted in microcephaly associated with defects in neurogenesis, particularly during cerebellar development (Frappart et al., 2007Frappart P.-O. Lee Y. Lamont J. McKinnon P.J. BRCA2 is required for neurogenesis and suppression of medulloblastoma.EMBO J. 2007; 26: 2732-2742Crossref PubMed Scopus (83) Google Scholar). The complex and multisystemic effects caused by defects in basic DNA-repair mechanisms are now well characterized. Research over many years has shown that neurodegenerative defects are often associated with repair syndromes, but it has been very difficult to establish the precise causative links between these processes. However, recent research on the neurodegenerative disorders ataxia with oculomotor apraxia 1 (AOA1) and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1), which are caused by dysfunction of Aprataxin (APTX) and tyrosyl-DNA phosphodiesterase 1 (TDP1), respectively, sheds new light on the underlying basis of DNA repair-associated neurodegeneration. AOA1 and SCAN1 are autosomal recessive cerebellar ataxias, but in contrast to A-T, their phenotypes are very much restricted to the nervous system. Recent findings indicate that neuronal cell death in AOA1 and SCAN1 is primarily due to the specific proofreading roles that Aprataxin and TDP1 play in the repair of DNA single-strand breaks (SSBs). This unprecedented correlation between molecular defect and neuron-specific impact may provide the missing link that allows us to begin to understand the relationship between neurodegeneration and defective DNA repair. In 1988, the neurological disorder “ataxia with oculomotor apraxia” was defined as a new syndrome. Although the neurological symptoms were similar to those exhibited by patients with A-T, the absence of multisystemic involvement indicated that this was a syndrome distinct from A-T (Aicardi et al., 1988Aicardi J. Barbosa C. Andermann E. Andermann F. Morcos R. Hghanem Q. Fukuyama Y. Awaya Y. Moe P. Ataxia-oculomotor apraxia: a syndrome mimicking ataxia-telangiectasia.Ann. Neurol. 1988; 24: 497-502Crossref PubMed Scopus (97) Google Scholar). Genetic studies subsequently revealed nonallelic heterogeneity in AOA, and two subgroups, named AOA1 (Date et al., 2001Date H. Onodera O. Tanaka H. Iwabuchi K. Uekawa K. Igarashi S. Koike R. Hiroi T. Yuasa T. Awaya Y. et al.Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.Nat. Genet. 2001; 29: 184-188Crossref PubMed Scopus (317) Google Scholar, Moreira et al., 2001Moreira M.C. Barbot C. Tachi N. Kozuka N. Uchida E. Gibson T. Mendonca P. Costa M. Barros J. Yanagisawa T. et al.The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.Nat. Genet. 2001; 29: 189-193Crossref PubMed Scopus (360) Google Scholar) and AOA2 (Moreira et al., 2004Moreira M.C. Klur S. Watanabe M. Nemeth A.H. Le Ber I. Moniz J.C. Tranchant C. Aubourg P. Tazir M. Schols L. et al.Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.Nat. Genet. 2004; 36: 225-227Crossref PubMed Scopus (367) Google Scholar), were described. The genetic defect associated with AOA1 maps to chromosome 9p13 (APTX, encoding Aprataxin) and that of AOA2 maps to 9q34 (SETX, encoding Senataxin, a homolog of a superfamily 1 RNA helicase known as Sen1 in yeast). AOA1 is characterized by cerebellar atrophy and sensorimotor neuropathy. Clinical manifestations include disturbances in motor coordination from an early age (2–6 years), oculomotor apraxia, loss of reflexes, and progressive disability leading to confinement to a wheelchair in adolescent life (Le Ber et al., 2003Le Ber I. Moreira M.C. Rivaud-Pechoux S. Chamayou C. Ochsner F. Kuntzer T. Tardieu M. Said G. Habert M.O. Demarquay G. et al.Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies.Brain. 2003; 126: 2761-2772Crossref PubMed Scopus (181) Google Scholar). Hypoalbuminemia (low blood albumin) and hypercholesterolemia (high levels of cholesterol in blood) are also common symptoms. AOA1 occurs in many ethnic groups but is most frequent in Japan and Portugal. Aprataxin is a 342 amino acid protein that localizes to the nucleus and nucleolus (Clements et al., 2004Clements P.M. Breslin C. Deeks E.D. Byrd P.J. Ju L. Bieganowski P. Brenner C. Moreira M.C. Taylor A.M. Caldecott K.W. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.DNA Repair (Amst.). 2004; 3: 1493-1502Crossref PubMed Scopus (154) Google Scholar, Date et al., 2001Date H. Onodera O. Tanaka H. Iwabuchi K. Uekawa K. Igarashi S. Koike R. Hiroi T. Yuasa T. Awaya Y. et al.Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.Nat. Genet. 2001; 29: 184-188Crossref PubMed Scopus (317) Google Scholar, Gueven et al., 2004Gueven N. Becherel O.J. Kijas A.W. Chen P. Howe O. Rudolph J.H. Gatti R. Date H. Onodera O. Taucher-Scholz G. et al.Aprataxin, a novel protein that protects against genotoxic stress.Hum. Mol. Genet. 2004; 13: 1081-1093Crossref PubMed Scopus (136) Google Scholar, Moreira et al., 2001Moreira M.C. Barbot C. Tachi N. Kozuka N. Uchida E. Gibson T. Mendonca P. Costa M. Barros J. Yanagisawa T. et al.The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.Nat. Genet. 2001; 29: 189-193Crossref PubMed Scopus (360) Google Scholar). It has three distinct domains: an N-terminal forkhead-associated (FHA) domain, a central histidine triad (HIT) domain, and a C2H2 zinc-finger (ZnF) domain at the C terminus (Figure 1). Detailed examination of these three domains has helped elucidate the repair role played by Aprataxin and its relevance for maintaining genome integrity in neuronal tissues. FHA domains represent phosphoprotein-binding modules and are found in a wide variety of prokaryotic and eukaryotic proteins (Durocher and Jackson, 2002Durocher D. Jackson S.P. The FHA domain.FEBS Lett. 2002; 513: 58-66Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar). 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Biol. Chem. 1999; 274: 24187-24194Crossref PubMed Scopus (185) Google Scholar). Aprataxin also interacts with XRCC1 and XRCC4 (Clements et al., 2004Clements P.M. Breslin C. Deeks E.D. Byrd P.J. Ju L. Bieganowski P. Brenner C. Moreira M.C. Taylor A.M. Caldecott K.W. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.DNA Repair (Amst.). 2004; 3: 1493-1502Crossref PubMed Scopus (154) Google Scholar, Luo et al., 2004Luo H. Chan D.W. Yang T. Rodriguez M. Chen B.P. Leng M. Mu J.J. Chen D. Songyang Z. Wang Y. et al.A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment.Mol. Cell. Biol. 2004; 24: 8356-8365Crossref PubMed Scopus (115) Google Scholar). Aprataxin-XRCC1 interactions are mediated by the FHA domain of Aprataxin and are abrogated by mutation of the conserved R29 residue (Clements et al., 2004Clements P.M. Breslin C. Deeks E.D. Byrd P.J. Ju L. Bieganowski P. Brenner C. Moreira M.C. Taylor A.M. Caldecott K.W. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.DNA Repair (Amst.). 2004; 3: 1493-1502Crossref PubMed Scopus (154) Google Scholar, Gueven et al., 2004Gueven N. Becherel O.J. Kijas A.W. Chen P. Howe O. Rudolph J.H. Gatti R. Date H. Onodera O. Taucher-Scholz G. et al.Aprataxin, a novel protein that protects against genotoxic stress.Hum. Mol. Genet. 2004; 13: 1081-1093Crossref PubMed Scopus (136) Google Scholar, Sano et al., 2004Sano Y. Date H. Igarashi S. Onodera O. Oyake M. Takahashi T. Hayashi A. Morimatsu M. Takahashi H. Makifuchi T. et al.Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein.Ann. Neurol. 2004; 55: 241-249Crossref PubMed Scopus (71) Google Scholar) or the C-terminal region of XRCC1 involving phosphoresidues S518, T519, and T523 (Figure 1) (Luo et al., 2004Luo H. Chan D.W. Yang T. Rodriguez M. Chen B.P. Leng M. Mu J.J. Chen D. Songyang Z. Wang Y. et al.A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment.Mol. Cell. Biol. 2004; 24: 8356-8365Crossref PubMed Scopus (115) Google Scholar). These amino acids are part of a cluster of CK2 phosphorylation sites in the linker region between the BRCTI and BRCTII domains in XRCC1 and are also critical for PNKP binding (Loizou et al., 2004Loizou J.I. El Khamisy S.F. Zlatanou A. Moore D.J. Chan D.W. Qin J. Sarno S. Meggio F. Pinna
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