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Aprataxin the new found

by candywhy at 05-31-2012, 03:51 PM 0 comments

Aprataxin the new found

Normal DNA damage repair mistakes will lead to many diseases, the most representative of the neurological disorders, genetic instability increases and cancer. In various types of DNA damage, single-strand breaks are the most common frequency of tens of thousands of cells every day, if the repair missed that cause disease. Recent discovery of a hereditary neurodegenerative venereal disease ataxia with eye movement lost able to disease (AOA1,) and a class of DNA damage repair proteins Aprataxin, encoding the protein gene APTX mutations cause AOA1 the occurrence of. AOA1 is a nervous system disorder, the major symptoms of cerebellar atrophy, sensory neuropathy, leading to loss of motor coordination, eye movement can not wait for disability lesions, patients will end up in a wheelchair. The known AOA1 widely distributed in the United Kingdom and the United States, Germany, France, Australia, Italian, Japanese, Portuguese and other countries. Clearly, revealing the molecular mechanism of this process is important.

Studies confirm Aprataxin is a single strand of a DNA damage repair enzyme, can be directly catalyzed removal of single-chain fracture pollution adduct on the 5'-AMP, the default interrupt the DNA ligation reaction can be reversed. Hnt3 protein of human Aprataxin in the fission yeast ortholog, and between them have the same basic biochemistry, molecular biology and functional characteristics. The article reported Hnt3 protein and a gap of DNA, the mechanism of the reaction product AMP complex three-dimensional structure and function of the structure. Formed a unique Hnt3 and DNA identification, the role and reaction of molecular platform for the ternary complex structure, reflecting the structural basis and molecular details Hnt3 reaction before and after the reaction product combined with state, including:

(1) Hnt3/Aprataxin is a special member of the widespread presence of histidine triad (HIT) superfamily of two structural units: the active site of HIT the domain, DNA binding sites ZF the domain, they are like two "molecular hand" each with DNA single-chain interactions across the 9-bp DNA double helix, covering the surface of the DNA main channel;

(2) during which the complex interactions of DNA bending, disturbance near the fracture gap "pollutants" (5'-adenosine acid) structure as valgus and "fragile", the formation of the activation of the substrate structure conducive to the reaction;

(3) On this basis, the HIT superfamily catalytic mechanism of removal of "pollution elements" to complete the incision blocking correction ;

(4) Hnt3 only with the DNA backbone role of non-sequence dependent, it is only sensitive to the polyadenylation of DNA breaks is not subject to the constraints of the chemical specificity of universal corrector. The structure study reveals Hnt3/Aprataxin fracture correction to the gap sensor and single-chain function through a complex interaction platform;

(5) The structure-based mechanistic conclusions have been reported with the current biochemical and molecular studies are basically the same, this structure reflects the mode of assembly of the physiological state of the DNA polyadenylation reveal the Hnt3/Aprataxin mutation lead to AOA1 neurological disorders major molecular mechanism and structural basis. At the same time, the study by site-directed mutagenesis and DNA interaction experiments, reveal a number of key amino acids the Hnt3 function, revealing Aprataxin a variety of pathogenic mutants in different ways (such as damage to its affinity with the substrate DNA and to adenosine enzyme activity to reduce the structural stability, etc.) interfere with DNA damage repair, which led to the structural basis of nervous system diseases.The study of neurodegenerative diseases in AOA1 mechanism provides a precise, quantitative knowledge, new principles, thus becoming an important foundation for innovative biomedical research and development of such diseases.