The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin

Moreira, Maria João; Barbot, Clara; Tachi, Nobutada; Kozuka, Naoki; Uchida, Eiji; Gibson, Toby J.; Mendonça, Pedro; Costa, Maria Manuela Ribeiro; Barros, José; Yanagisawa, Takayuki; Watanabe, Mitsunori; Ikeda, Yoshio; Akiyama, Masashi; Nagata, Tetsuya; Coutinho, Paula; Sequeiros, Jorge; Kœnig, M.

doi:10.1038/ng1001-189

Cited by 409 publications

(325 citation statements)

References 21 publications

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“…Instead, removal of this 5'blocking lesion is most likely the result of strand displacement and Fen1-mediated hydrolysis and would be shuttled into the long-patch complex depicted in Fig 2, bottom right complex. In 2001, the gene responsible for ataxia-ocular apraxia 1 (AOA1), a neurological disorder similar to ataxia-telangiectasia, was identified. The protein was named aprataxin (APTX) and is found to share a distant homology with PNKP [84]. Interestingly, APTX also interacts in vitro and in vivo with XRCC1 [72][73][74][75][76] and co-immunoprecipitated with PARP1 [73,74].…”

Section: Gap Tailoringmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

387

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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Section: Gap Tailoringmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

387

374

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“…Despite literature that is sparse outside of Portugal (27) and Japan (28), AOA has been found in many ethnic groups and does not appear to be a Portuguese or Japanese disease but rather a disease that is rare but ubiquitous (26). Two groups succeeded in positional cloning of an AOA disease locus to the APTX gene encoding Aprataxin on 9p13 (29,30).…”

Section: Aprataxin: a Zn-finger-containing Hint Family Member That Ismentioning

confidence: 99%

“…Human Aprataxin is expressed in two splice forms (30). The minor splice form encodes a predicted polypeptide of 168 amino acids consisting of a Hint domain and an apparent C(2)H (2) zinc finger C-terminal to the Hint domain (29,30).…”

Section: Aprataxin: a Zn-finger-containing Hint Family Member That Ismentioning

confidence: 99%

“…Residues 6 through 102 of the N-terminus of Aprataxin are 41% identical with the N-terminus of human polynucleotide kinase (PNK), an enzyme with 5′-DNA kinase, 3′-phosphatase activity that is located C-terminal to this domain (33,34). The observation that PNK and Aprataxin share an N-terminal domain suggested that Aprataxin may have a role in single strand break repair (30). Indeed the PNK and Aprataxin N-terminal domain, termed PANT (30), was recognized as a forkhead-associated (FHA) domain by Keith Caldecott (personal communication).…”

Section: Aprataxin: a Zn-finger-containing Hint Family Member That Ismentioning

confidence: 99%

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Hint, Fhit, and GalT: Function, Structure, Evolution, and Mechanism of Three Branches of the Histidine Triad Superfamily of Nucleotide Hydrolases and Transferases

2002

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HIT (histidine triad)1 proteins, named for a motif related to the sequence HφHφHφφ, (φ a hydrophobic amino acid) are a superfamily of nucleotide hydrolases and transferases, which act on the α-phosphate of ribonucleotides, and contain a ∼30 kDa domain that is typically either a homodimer of ∼15 kDa polypeptides with two active-sites or an internally, imperfectly repeated polypeptide that retains a single HIT active site. On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins can be classified into the Hint branch, which consists of adenosine 5′-monophosphoramide hydrolases, the Fhit branch, which consists of diadenosine polyphosphate hydrolases, and the GalT branch, which consists of specific nucleoside monophosphate transferases including galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylylsulfate:phosphate adenylytransferase. At least one human representative of each branch is lost in human diseases. Aprataxin, a Hint branch hydrolase, is mutated in ataxia-oculomotor apraxia syndrome. Fhit is lost early in development of many epithelially derived tumors. GalT is deficient in galactosemia. Additionally, ASW is an avian Hint family member that has evolved to have unusual gene expression properties and the complete loss of its nucleotide binding-site. The potential roles of ASW and Hint in avian sexual development are discussed in an accompanying manuscript. Here we review what is known about biological activities of HIT proteins, the structural and biochemical bases for their functions, and propose a new enzyme mechanism for Hint and Fhit that may account for the differences between HIT hydrolases and transferases. Mammalian Hint and GalT Structurally Define the HIT SuperfamilyGalactose-1-phosphate uridylyltransferase (GalT), the second enzyme in the Leloir pathway of galactose utilization (1), was crystallized and its structure determined to understand the mechanistic basis for transferring UMP between glucose-1-phosphate and galactose-1-phosphate (2-4). Histidine triad nucleotide-binding protein (Hint), purified as a purine nucleoside/nucleotide-binding protein from rabbit heart cytosol (5) and shown to have a widely conserved sequence (6), was crystallized and its structure determined to establish whether the conserved sequence formed the basis for a new mode of nucleotide-binding (7). GalT (2) and Hint are both dimers (8) but the GalT monomer is more than twice the size of the Hint dimer. Though GalT (9) and Hint (6) homologs could be cloned by similarity and the crystal structures (2,8) co-existed in protein databases, mutual similarity was not noted until inspection of the rabbit Hint crystal structure (7) and computational analysis (10) indicated that a GalT monomer and a Hint dimer can be superimposed and that their nucleotide-binding sites retain some of the same residues for binding a nucleoside monophosphate (7) (Figure 1). The level of sequence similarity of Hint and GalT is difficult to distinguish from n...

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“…In addition, seizures in the affected sister disappeared on CoQ 10 therapy and her anti-convulsant medication was discontinued (Musumeci et al, 2001). In these 3 patients, we demonstrated that CoQ 10 deficiency was secondary to a stop codon mutation in the APTX gene, which is known to cause ataxia-oculomotor-aprataxia 1 (AOA1) (Quinzii et al, 2005,Date et al, 2001Moreira et al, 2001). Results from measuring CoQ 10 concentration in skeletal muscle from 12 additional patients from 6 different families with AOA1 confirmed this data (data not published).…”

mentioning

confidence: 94%

CoQ10 deficiency diseases in adults

2007

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The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin

Cited by 409 publications

References 21 publications

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Hint, Fhit, and GalT: Function, Structure, Evolution, and Mechanism of Three Branches of the Histidine Triad Superfamily of Nucleotide Hydrolases and Transferases

CoQ10 deficiency diseases in adults

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