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Keith W Caldecott - One of the best experts on this subject based on the ideXlab platform.
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versatility in phospho dependent molecular recognition of the xrcc1 and xrcc4 dna damage scaffolds by Aprataxin family fha domains
DNA Repair, 2015Co-Authors: Amy L Cherry, Keith W Caldecott, Timothy J Nott, Geoffrey Kelly, Stuart L Rulten, Stephen J SmerdonAbstract:Aprataxin, Aprataxin and PNKP-like factor (APLF) and polynucleotide kinase phosphatase (PNKP) are key DNA-repair proteins with diverse functions but which all contain a homologous forkhead-associated (FHA) domain. Their primary binding targets are casein kinase 2-phosphorylated forms of the XRCC1 and XRCC4 scaffold molecules which respectively coordinate single-stranded and double-stranded DNA break repair pathways. Here, we present the high-resolution X-ray structure of a complex of phosphorylated XRCC4 with APLF, the most divergent of the three FHA domain family members. This, combined with NMR and biochemical analysis of Aprataxin and APLF binding to singly and multiply-phosphorylated forms of XRCC1 and XRCC4, and comparison with PNKP reveals a pattern of distinct but overlapping binding specificities that are differentially modulated by multi-site phosphorylation. Together, our data illuminate important differences between activities of the three phospho-binding domains, in spite of a close evolutionary relationship between them.
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synergistic decrease of dna single strand break repair rates in mouse neural cells lacking both tdp1 and Aprataxin
DNA Repair, 2009Co-Authors: Sherif F Elkhamisy, Sachin Katyal, Limei Ju, Peter J Mckinnon, Poorvi Patel, Keith W CaldecottAbstract:Ataxia oculomotor apraxia-1 (AOA1) is an autosomal recessive neurodegenerative disease that results from mutations of Aprataxin (APTX). APTX associates with the DNA single- and double-strand break repair machinery and is able to remove AMP from 5′-termini at DNA strand breaks in vitro. However, attempts to establish a DNA strand break repair defect in APTX-defective cells have proved conflicting and unclear. We reasoned that this may reflect that DNA strand breaks with 5′-AMP represent only a minor subset of breaks induced in cells, and/or the availability of alternative mechanisms for removing AMP from 5′-termini. Here, we have attempted to increase the dependency of chromosomal single- and double-strand break repair on Aprataxin activity by slowing the rate of repair of 3′-termini in Aprataxin-defective neural cells, thereby increasing the likelihood that the 5′-termini at such breaks become adenylated and/or block alternative repair mechanisms. To do this, we generated a mouse model in which APTX is deleted together with tyrosyl DNA phosphodiesterase (TDP1), an enzyme that repairs 3′-termini at a subset of single-strand breaks (SSBs), including those with 3′-topoisomerase-1 (Top1) peptide. Notably, the global rate of repair of oxidative and alkylation-induced SSBs was significantly slower in Tdp1−/−/Aptx−/− double knockout quiescent mouse astrocytes compared with Tdp1−/− or Aptx−/− single knockouts. In contrast, camptothecin-induced Top1-SSBs accumulated to similar levels in Tdp1−/− and Tdp1−/−/Aptx−/− double knockout astrocytes. Finally, we failed to identify a measurable defect in double-strand break repair in Tdp1−/−, Aptx−/− or Tdp1−/−/Aptx−/− astrocytes. These data provide direct evidence for a requirement for Aprataxin during chromosomal single-strand break repair in primary neural cells lacking Tdp1.
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short patch single strand break repair in ataxia oculomotor apraxia 1
Biochemical Society Transactions, 2009Co-Authors: John J Reynolds, Sherif F Elkhamisy, Keith W CaldecottAbstract:AOA1 (ataxia oculomotor apraxia-1) results from mutations in Aprataxin, a component of DNA strand break repair that removes AMP from 5-termini. In the present article, we provide an overview of this disease and review recent experiments demonstrating that short-patch repair of oxidative single-strand breaks in AOA1 cell extracts bypasses the point of Aprataxin action and stalls at the final step of DNA ligation, resulting in accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of non-adenylated DNA ligase and short-patch single-strand break repair can be restored in AOA1 extracts, independently of Aprataxin, by addition of recombinant DNA ligase.
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defective dna ligation during short patch single strand break repair in ataxia oculomotor apraxia 1
Molecular and Cellular Biology, 2009Co-Authors: John J Reynolds, Sherif F Elkhamisy, Sachin Katyal, Paula M Clements, Peter J Mckinnon, Keith W CaldecottAbstract:Ataxia oculomotor apraxia 1 (AOA1) results from mutations in Aprataxin, a component of DNA strand break repair that removes AMP from 5' termini. Despite this, global rates of chromosomal strand break repair are normal in a variety of AOA1 and other Aprataxin-defective cells. Here we show that short-patch single-strand break repair (SSBR) in AOA1 cell extracts bypasses the point of Aprataxin action at oxidative breaks and stalls at the final step of DNA ligation, resulting in the accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of nonadenylated DNA ligase, and short-patch SSBR can be restored in AOA1 extracts, independently of Aprataxin, by the addition of recombinant DNA ligase. Since adenylated nicks are substrates for long-patch SSBR, we reasoned that this pathway might in part explain the apparent absence of a chromosomal SSBR defect in Aprataxin-defective cells. Indeed, whereas chemical inhibition of long-patch repair did not affect SSBR rates in wild-type mouse neural astrocytes, it uncovered a significant defect in Aptx(-/-) neural astrocytes. These data demonstrate that Aprataxin participates in chromosomal SSBR in vivo and suggest that short-patch SSBR arrests in AOA1 because of insufficient nonadenylated DNA ligase.
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APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks.
Molecular and Cellular Biology, 2007Co-Authors: Natasha Iles, Stuart L Rulten, Sherif F. El-khamisy, Keith W CaldecottAbstract:Aprataxin and polynucleotide kinase (PNK) are DNA end processing factors that are recruited into the DNA single- and double-strand break repair machinery through phosphorylation-specific interactions with XRCC1 and XRCC4, respectively. These interactions are mediated through a divergent class of forkhead-associated (FHA) domain that binds to peptide sequences in XRCC1 and XRCC4 that are phosphorylated by casein kinase 2 (CK2). Here, we identify the product of the uncharacterized open reading frame C2orf13 as a novel member of this FHA domain family of proteins and we denote this protein APLF (Aprataxin- and PNK-like factor). We show that APLF interacts with XRCC1 in vivo and in vitro in a manner that is stimulated by CK2. Yeast two-hybrid analyses suggest that APLF also interacts with the double-strand break repair proteins XRCC4 and XRCC5 (Ku86). We also show that endogenous and yellow fluorescent protein-tagged APLF accumulates at sites of H2O2 or UVA laser-induced chromosomal DNA damage and that this is achieved through at least two mechanisms: one that requires the FHA domain-mediated interaction with XRCC1 and a second that is independent of XRCC1 but requires a novel type of zinc finger motif located at the C terminus of APLF. Finally, we demonstrate that APLF is phosphorylated in a DNA damage- and ATM-dependent manner and that the depletion of APLF from noncycling human SH-SY5Y neuroblastoma cells reduces rates of chromosomal DNA strand break repair following ionizing radiation. These data identify APLF as a novel component of the cellular response to DNA strand breaks in human cells.
Sherif F Elkhamisy - One of the best experts on this subject based on the ideXlab platform.
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synergistic decrease of dna single strand break repair rates in mouse neural cells lacking both tdp1 and Aprataxin
DNA Repair, 2009Co-Authors: Sherif F Elkhamisy, Sachin Katyal, Limei Ju, Peter J Mckinnon, Poorvi Patel, Keith W CaldecottAbstract:Ataxia oculomotor apraxia-1 (AOA1) is an autosomal recessive neurodegenerative disease that results from mutations of Aprataxin (APTX). APTX associates with the DNA single- and double-strand break repair machinery and is able to remove AMP from 5′-termini at DNA strand breaks in vitro. However, attempts to establish a DNA strand break repair defect in APTX-defective cells have proved conflicting and unclear. We reasoned that this may reflect that DNA strand breaks with 5′-AMP represent only a minor subset of breaks induced in cells, and/or the availability of alternative mechanisms for removing AMP from 5′-termini. Here, we have attempted to increase the dependency of chromosomal single- and double-strand break repair on Aprataxin activity by slowing the rate of repair of 3′-termini in Aprataxin-defective neural cells, thereby increasing the likelihood that the 5′-termini at such breaks become adenylated and/or block alternative repair mechanisms. To do this, we generated a mouse model in which APTX is deleted together with tyrosyl DNA phosphodiesterase (TDP1), an enzyme that repairs 3′-termini at a subset of single-strand breaks (SSBs), including those with 3′-topoisomerase-1 (Top1) peptide. Notably, the global rate of repair of oxidative and alkylation-induced SSBs was significantly slower in Tdp1−/−/Aptx−/− double knockout quiescent mouse astrocytes compared with Tdp1−/− or Aptx−/− single knockouts. In contrast, camptothecin-induced Top1-SSBs accumulated to similar levels in Tdp1−/− and Tdp1−/−/Aptx−/− double knockout astrocytes. Finally, we failed to identify a measurable defect in double-strand break repair in Tdp1−/−, Aptx−/− or Tdp1−/−/Aptx−/− astrocytes. These data provide direct evidence for a requirement for Aprataxin during chromosomal single-strand break repair in primary neural cells lacking Tdp1.
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short patch single strand break repair in ataxia oculomotor apraxia 1
Biochemical Society Transactions, 2009Co-Authors: John J Reynolds, Sherif F Elkhamisy, Keith W CaldecottAbstract:AOA1 (ataxia oculomotor apraxia-1) results from mutations in Aprataxin, a component of DNA strand break repair that removes AMP from 5-termini. In the present article, we provide an overview of this disease and review recent experiments demonstrating that short-patch repair of oxidative single-strand breaks in AOA1 cell extracts bypasses the point of Aprataxin action and stalls at the final step of DNA ligation, resulting in accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of non-adenylated DNA ligase and short-patch single-strand break repair can be restored in AOA1 extracts, independently of Aprataxin, by addition of recombinant DNA ligase.
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defective dna ligation during short patch single strand break repair in ataxia oculomotor apraxia 1
Molecular and Cellular Biology, 2009Co-Authors: John J Reynolds, Sherif F Elkhamisy, Sachin Katyal, Paula M Clements, Peter J Mckinnon, Keith W CaldecottAbstract:Ataxia oculomotor apraxia 1 (AOA1) results from mutations in Aprataxin, a component of DNA strand break repair that removes AMP from 5' termini. Despite this, global rates of chromosomal strand break repair are normal in a variety of AOA1 and other Aprataxin-defective cells. Here we show that short-patch single-strand break repair (SSBR) in AOA1 cell extracts bypasses the point of Aprataxin action at oxidative breaks and stalls at the final step of DNA ligation, resulting in the accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of nonadenylated DNA ligase, and short-patch SSBR can be restored in AOA1 extracts, independently of Aprataxin, by the addition of recombinant DNA ligase. Since adenylated nicks are substrates for long-patch SSBR, we reasoned that this pathway might in part explain the apparent absence of a chromosomal SSBR defect in Aprataxin-defective cells. Indeed, whereas chemical inhibition of long-patch repair did not affect SSBR rates in wild-type mouse neural astrocytes, it uncovered a significant defect in Aptx(-/-) neural astrocytes. These data demonstrate that Aprataxin participates in chromosomal SSBR in vivo and suggest that short-patch SSBR arrests in AOA1 because of insufficient nonadenylated DNA ligase.
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the neurodegenerative disease protein Aprataxin resolves abortive dna ligation intermediates
Nature, 2006Co-Authors: Ivan Ahel, Sherif F Elkhamisy, Sachin Katyal, Paula M Clements, Keith W Caldecott, Peter J Mckinnon, Ulrich Rass, Stephen C WestAbstract:Ataxia oculomotor apraxia-1 (AOA1) is a neurological disorder caused by mutations in the gene (APTX) encoding Aprataxin1, 2. Aprataxin is a member of the histidine triad (HIT) family of nucleotide hydrolases and transferases3, and inactivating mutations are largely confined to this HIT domain. Aprataxin associates with the DNA repair proteins XRCC1 and XRCC4, which are partners of DNA ligase III and ligase IV, respectively4, 5, 6, 7, suggestive of a role in DNA repair. Consistent with this, APTX-defective cell lines are sensitive to agents that cause single-strand breaks and exhibit an increased incidence of induced chromosomal aberrations4, 5, 8. It is not, however, known whether Aprataxin has a direct or indirect role in DNA repair, or what the physiological substrate of Aprataxin might be. Here we show, using purified Aprataxin protein and extracts derived from either APTX-defective chicken DT40 cells or Aptx-/- mouse primary neural cells, that Aprataxin resolves abortive DNA ligation intermediates. Specifically, Aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5'-phosphate termini at single-strand nicks and gaps, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. These data indicate that neurological disorders associated with APTX mutations may be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events.
Martin F Lavin - One of the best experts on this subject based on the ideXlab platform.
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Aprataxin poly adp ribose polymerase 1 parp 1 and apurinic endonuclease 1 ape1 function together to protect the genome against oxidative damage
Human Molecular Genetics, 2009Co-Authors: Olivier J Becherel, Burkhard Jakob, Gisela Taucherscholz, Martin F Lavin, Janelle L Harris, Grigory L DianovAbstract:Aprataxin, defective in the neurodegenerative disorder ataxia oculomotor apraxia type 1 (AOA1), is a DNA repair protein that processes the product of abortive ligations, 5′ adenylated DNA. In addition to its interaction with the single-strand break repair protein XRCC1, Aprataxin also interacts with poly-ADP ribose polymerase 1 (PARP-1), a key player in the detection of DNA single-strand breaks. Here, we reveal reduced expression of PARP-1, apurinic endonuclease 1 (APE1) and OGG1 in AOA1 cells and demonstrate a requirement for PARP-1 in the recruitment of Aprataxin to sites of DNA breaks. While inhibition of PARP activity did not affect Aprataxin activity in vitro, it retarded its recruitment to sites of DNA damage in vivo. We also demonstrate the presence of elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between Aprataxin, PARP-1, APE-1 and OGG1 in the DNA damage response. These data support both direct and indirect modulating functions for Aprataxin on base excision repair.
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nucleolar localization of Aprataxin is dependent on interaction with nucleolin and on active ribosomal dna transcription
Human Molecular Genetics, 2006Co-Authors: Olivier J Becherel, Nuri Gueven, Geoff W Birrell, Valeerie Schreiber, Amila Suraweera, Burkhard Jakob, Gisela Taucherscholz, Martin F LavinAbstract:The APTX gene, mutated in patients with the neurological disorder ataxia with oculomotor apraxia type 1 (AOA1), encodes a novel protein Aprataxin. We describe here, the interaction and interdependence between Aprataxin and several nucleolar proteins, including nucleolin, nucleophosmin and upstream binding factor-1 (UBF-1), involved in ribosomal RNA (rRNA) synthesis and cellular stress signalling. Interaction between Aprataxin and nucleolin occurred through their respective N-terminal regions. In AOA1 cells lacking Aprataxin, the stability of nucleolin was significantly reduced. On the other hand, down-regulation of nucleolin by RNA interference did not affect Aprataxin protein levels but abolished its nucleolar localization suggesting that the interaction with nucleolin is involved in its nucleolar targeting. GFP-Aprataxin fusion protein co-localized with nucleolin, nucleophosmin and UBF-1 in nucleoli and inhibition of ribosomal DNA transcription altered the distribution of Aprataxin in the nucleolus, suggesting that the nature of the nucleolar localization of Aprataxin is also dependent on ongoing rRNA synthesis. In vivo rRNA synthesis analysis showed only a minor decrease in AOA1 cells when compared with controls cells. These results demonstrate a cross-dependence between Aprataxin and nucleolin in the nucleolus and while Aprataxin does not appear to be directly involved in rRNA synthesis its nucleolar localization is dependent on this synthesis.
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Aprataxin forms a discrete branch in the hit histidine triad superfamily of proteins with both dna rna binding and nucleotide hydrolase activities
Journal of Biological Chemistry, 2006Co-Authors: Amanda W Kijas, Janelle L Harris, Jonathan M Harris, Martin F LavinAbstract:Abstract Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset autosomal recessive spinocerebellar ataxia with a defect in the protein Aprataxin, implicated in the response of cells to DNA damage. We describe here the expression of a recombinant form of Aprataxin and show that it has dual DNA binding and nucleotide hydrolase activities. This protein binds to double-stranded DNA with high affinity but is also capable of binding double-stranded RNA and single-strand DNA, with increased affinity for hairpin structures. No increased binding was observed with a variety of DNA structures mimicking intermediates in DNA repair. The DNA binding observed here was not dependent on zinc, and the addition of exogenous zinc abolished DNA binding. We also demonstrate that Aprataxin hydrolyzes with similar efficiency the model histidine triad nucleotide-binding protein substrate, AMPNH2, and the Fragile histidine triad protein substrate, Ap4A. These activities were significantly reduced in the presence of duplex DNA and to a lesser extent in the presence of single-strand DNA, and removal of the N-terminal Forkhead associated domain did not alter activity. Finally, comparison of sequence relationships between the histidine triad superfamily members shows that Aprataxin forms a distinct branch in this superfamily. In addition to its capacity for nucleotide binding and hydrolysis, the observation that it also binds DNA and RNA adds a new dimension to this superfamily of proteins and provides further support for a role for Aprataxin in the cellular response to DNA damage.
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Aprataxin forms a discrete branch in the HIT (histidine triad) superfamily of proteins with both DNA/RNA binding and nucleotide hydrolase activities
Journal of Biological Chemistry, 2006Co-Authors: Amanda W Kijas, Janelle L Harris, Jonathan M Harris, Martin F LavinAbstract:Abstract Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset autosomal recessive spinocerebellar ataxia with a defect in the protein Aprataxin, implicated in the response of cells to DNA damage. We describe here the expression of a recombinant form of Aprataxin and show that it has dual DNA binding and nucleotide hydrolase activities. This protein binds to double-stranded DNA with high affinity but is also capable of binding double-stranded RNA and single-strand DNA, with increased affinity for hairpin structures. No increased binding was observed with a variety of DNA structures mimicking intermediates in DNA repair. The DNA binding observed here was not dependent on zinc, and the addition of exogenous zinc abolished DNA binding. We also demonstrate that Aprataxin hydrolyzes with similar efficiency the model histidine triad nucleotide-binding protein substrate, AMPNH2, and the Fragile histidine triad protein substrate, Ap4A. These activities were significantly reduced in the presence of duplex DNA and to a lesser extent in the presence of single-strand DNA, and removal of the N-terminal Forkhead associated domain did not alter activity. Finally, comparison of sequence relationships between the histidine triad superfamily members shows that Aprataxin forms a distinct branch in this superfamily. In addition to its capacity for nucleotide binding and hydrolysis, the observation that it also binds DNA and RNA adds a new dimension to this superfamily of proteins and provides further support for a role for Aprataxin in the cellular response to DNA damage.
Scott R Williams - One of the best experts on this subject based on the ideXlab platform.
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molecular underpinnings of Aprataxin rna dna deadenylase function and dysfunction in neurological disease
Progress in Biophysics & Molecular Biology, 2015Co-Authors: Matthew J. Schellenberg, P P Tumbale, Scott R WilliamsAbstract:Abstract Eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions act as molecular checkpoint for DNA damage and create 5′-adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA single strand break repair (SSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder Ataxia with Oculomotor Apraxia 1 (AOA1), acts as a DNA ligase “proofreader” to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage responses. Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction, and is providing insights into the molecular bases of APTX deficiency in AOA1.
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Aprataxin resolves adenylated rna dna junctions to maintain genome integrity
Nature, 2014Co-Authors: P P Tumbale, Jessica S Williams, Matthew J. Schellenberg, Thomas A. Kunkel, Scott R WilliamsAbstract:This study shows that Aprataxin, encoded by a gene mutated in the neurodegenerative disorder AOA1, can remove the 5′ AMP from RNA–DNA junctions; this RNA–DNA damage response promotes cell survival. Occasionally during DNA replication or repair, a ribonucleotide rather than a deoxyribonucleotide is inserted into the polymer. To reverse this, RNase H2 first cleaves the RNA-DNA junction. This nick is a poor substrate for DNA ligase, however, and an abortive 5′ adenylated end is frequently formed. Scott Williams and colleagues show that the DNA strand-break repair protein Aprataxin can remove the 5′ AMP from such RNA-DNA junctions. This RNA-DNA damage response promotes cell survival. Since mutations in the APTX gene encoding Aprataxin cause the neurological disorder AOA1 (ataxia oculomotor apraxia-1), these findings suggest that the accumulation of toxic adenylated 5′ ends at ribonucleotides in DNA may cause neurological diseases. Faithful maintenance and propagation of eukaryotic genomes is ensured by three-step DNA ligation reactions used by ATP-dependent DNA ligases1,2. Paradoxically, when DNA ligases encounter nicked DNA structures with abnormal DNA termini, DNA ligase catalytic activity can generate and/or exacerbate DNA damage through abortive ligation that produces chemically adducted, toxic 5′-adenylated (5′-AMP) DNA lesions3,4,5,6. Aprataxin (APTX) reverses DNA adenylation but the context for deadenylation repair is unclear. Here we examine the importance of APTX to RNase-H2-dependent excision repair (RER) of a lesion that is very frequently introduced into DNA, a ribonucleotide. We show that ligases generate adenylated 5′ ends containing a ribose characteristic of RNase H2 incision. APTX efficiently repairs adenylated RNA–DNA, and acting in an RNA–DNA damage response (RDDR), promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RER. Structure–function studies of human APTX–RNA–DNA–AMP–Zn complexes define a mechanism for detecting and reversing adenylation at RNA–DNA junctions. This involves A-form RNA binding, proper protein folding and conformational changes, all of which are affected by heritable APTX mutations in ataxia with oculomotor apraxia 1. Together, these results indicate that accumulation of adenylated RNA–DNA may contribute to neurological disease.
Mariaceu Moreira - One of the best experts on this subject based on the ideXlab platform.
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chapter 10 recessive ataxia plus oculomotor apraxia syndromes
Blue Books of Neurology, 2007Co-Authors: Michel Koenig, Mariaceu MoreiraAbstract:Publisher Summary Ataxia with oculomotor apraxia (AOA) is a newly recognized group of recessive ataxias that associate ataxia due to cerebellar atrophy with peripheral sensorimotor neuropathy. Unlike what the name suggests, oculomotor apraxia is not an absolute feature of AOA but is a useful diagnostic aid when present. This chapter discusses recessive ataxia plus oculomotor apraxia syndromes. Molecular genetic studies have delineated a novel group of recessive ataxias defined by the association of cerebellar atrophy and peripheral sensorimotor neuropathy. This group includes ataxia with oculomotor apraxia form 1, defined by late hypoalbuminemia and hypercholesterolemia; ataxia with oculomotor apraxia form 2, defined by moderately elevated serum α-fetoprotein (AFP); ataxia-telangiectasia-like disease without elevated serum AFP; and spinocerebellar ataxia with neuropathy (SCAN1), also associated with late hypoalbuminemia. For all four inherited diseases, the gene encodes for a nuclear protein (Aprataxin, senataxin, MRE11, and tyrosyl-DNA phosphodiesterase, respectively), which is or may be involved in DNA repair, although the disease causing mutations do not result in cancer predisposition.
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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, 2004Co-Authors: Paula M Clements, Mariaceu Moreira, Malcolm A R Taylor, Claire Breslin, Limei Ju, Pawel Bieganowski, Charles Brenner, Emma D. Deeks, Philip J Byrd, Keith W CaldecottAbstract:Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding Aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, Aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.
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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, 2004Co-Authors: Paula M Clements, Mariaceu Moreira, Claire Breslin, Limei Ju, Pawel Bieganowski, Charles Brenner, Emma D. Deeks, A. Malcolm R. Taylor, Philip J Byrd, Keith W CaldecottAbstract:Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding Aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, Aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.
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Aprataxin gene mutations in Tunisian families
Neurology, 2004Co-Authors: Rim Amouri, Mariaceu Moreira, G. El Euch, C. Barhoumi, Mourad Zouari, Michel Koenig, Samir Belal, Mounir Kefi, Fayçel HentatiAbstract:The authors report clinical and genetic study of 13 patients from three unrelated Tunisian families with an early onset cerebellar ataxia associated with oculomotor apraxia. Cerebellar ataxia with oculomotor apraxia 1 (AOA1) represents a clinically heterogeneous disease caused by mutations in the Aprataxin gene. Two novel mutations were identified, the complete deletion of the gene, which seems to not correlate with an increased severity of the disease, and a splice mutation on the acceptor splice site of exon 7.
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cerebellar ataxia with oculomotor apraxia type 1 clinical and genetic studies
Brain, 2003Co-Authors: Mariaceu Moreira, Celine Chamayou, Marie-odile Habert, F. Ochsner, Thierry Kuntzer, Geneviève Demarquay, Gérard Said, Sophie Rivaudpechoux, Marc Tardieu, Christian TannierAbstract:Summary Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes Aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the Aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 6 4.8 years (range 2‐18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades’. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich’s ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington’s disease.