Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of mammalian cells to agents that induce DNA double-strand breaks typically results in both reciprocal and nonreciprocal chromosome translocations. Over the past decade, breakpoint junctions of a significant number of translocations and other genomic rearrangements, both in clinical tumors and in experimental models, have been analyzed at the DNA sequence level. Based on these data, reasonable inferences regarding the biochemical mechanisms involved in translocations can be drawn. In a few cases, breakpoints have been shown to correlate with sites of double-strand cleavage by agents to which the cells or patients have been exposed, including exogenous rare-cutting endonucleases, radiomimetic compounds, and topoisomerase inhibitors. These results confirm that translocations primarily reflect misjoining of the exchanged ends of two or more double-strand breaks. Many junctions show significant loss of DNA sequence at the breakpoints, suggesting exonucleolytic degradation of DNA ends prior to joining. The size and frequency of these deletions varies widely, both between experimental systems, and among individual events in a single system. Homologous recombination between repetitive DNA sequences does not appear to be a major pathway for translocations associated with double-strand breaks. Rather, the general features of the junction sequences, particularly the high frequency small terminal deletions, the apparent splicing of DNA ends at microhomologies, and gap-filling on aligned double-strand break ends, are consistent with the known biochemical properties of the classical nonhomologous end joining pathway involving DNA-dependent protein kinase, XRCC4 and DNA ligase IV. Nevertheless, cells with deficiencies in this pathway still exhibit translocations, with grossly similar junction sequences, suggesting an alternative but less conservative end joining pathway. Although evidence for participation of specific DNA end processing enzymes in formation of translocations is largely circumstantial, likely candidates include DNA polymerases lambda and mu, Artemis nuclease, polynucleotide kinase/phosphatase, tyrosyl-DNA phosphodiesterase, DNase III, Werner syndrome protein, and the Mre11/Rad50/NBS1 complex.
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PMID:Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks. 1682 25

Tyrosyl-DNA-phosphodiesterase 1 (Tdp1) can disjoin peptides covalently bound to DNA. We assessed the role of Tdp1 in nonhomologous end joining (NHEJ) and found that linear DNA molecules with 5' extensions showed a high frequency of misrepair in Deltatdp1 cells. The joining errors in Deltatdp1 cells were predominantly 2-4 nucleotide insertions. Ends with 3' extensions or blunt ends did not show enhanced frequencies of errors, although Deltatdp1 cells repaired blunt DNA ends with greater efficiency than WT cells. We found that insertions required Ku80 and DNA ligase IV, as well as polymerase IV. Our results show that yeast Tdp1 is a component of the NHEJ pathway. We suggest that Tdp1p 3' nucleosidase activity regulates the processing of DNA ends by generating a 3' phosphate, thereby restricting the ability of polymerases and other enzymes from acting at DNA ends. In support of this model, we found that overexpression of Tpp1, a yeast DNA 3' phosphatase, also leads to a higher frequency of insertions, suggesting that the generation of a 3' phosphate is a key step in Tdp1-mediated error prevention during NHEJ.
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PMID:Yeast Tdp1 regulates the fidelity of nonhomologous end joining. 2016 Jan 11

The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. In tumor cells, the ability to repair DSBs predicts response to radiation and many cytotoxic anti-cancer drugs. DSB repair pathways include homologous recombination and non-homologous end joining (NHEJ). NHEJ is a template-independent mechanism, yet many NHEJ repair products carry limited genetic changes, which suggests that NHEJ includes mechanisms to minimize error. Proteins required for mammalian NHEJ include Ku70/80, the DNA-dependent protein kinase (DNA-PKcs), XLF/Cernunnos and the XRCC4:DNA ligase IV complex. NHEJ also utilizes accessory proteins that include DNA polymerases, nucleases, and other end-processing factors. In yeast, mutations of tyrosyl-DNA phosphodiesterase (TDP1) reduced NHEJ fidelity. TDP1 plays an important role in repair of topoisomerase-mediated DNA damage and 3'-blocking DNA lesions, and mutation of the human TDP1 gene results in an inherited human neuropathy termed SCAN1. We found that human TDP1 stimulated DNA binding by XLF and physically interacted with XLF to form TDP1:XLF:DNA complexes. TDP1:XLF interactions preferentially stimulated TDP1 activity on dsDNA as compared to ssDNA. TDP1 also promoted DNA binding by Ku70/80 and stimulated DNA-PK activity. Because Ku70/80 and XLF are the first factors recruited to the DSB at the onset of NHEJ, our data suggest a role for TDP1 during the early stages of mammalian NHEJ.
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PMID:TDP1 promotes assembly of non-homologous end joining protein complexes on DNA. 2584 Nov 1