95 research outputs found
Intraluminal vesicle trafficking is involved in the secretion of base excision repair protein APE1
No full textHuman AP-endonuclease (Ape1) activity on telomeric G4 structures is modulated by acetylatable lysine residues in the N-terminal sequence
No full textLoss of telomeres stability is a hallmark of cancer cells. Exposed telomeres are prone to aberrant end joining reactions leading to chromosomal fusions and translocations. Human telomeres contain repeated TTAGGG elements, in which the 3' exposed strand may adopt a G-quadruplex (G4) structure. The guanine-rich regions of telomeres are hotspots for oxidation forming 8-oxoguanine, a lesion that is handled by the base excision repair (BER) pathway. One key player of this pathway is Ape1, the main human endonuclease processing abasic sites. Recent evidences showed an important role for Ape1 in telomeric physiology, but the molecular details regulating Ape1 enzymatic activities on G4-telomeric sequences are lacking. Through a combination of in vitro assays, we demonstrate that Ape1 can bind and process different G4 structures and that this interaction involves specific acetylatable lysine residues (i.e. K-27/31/32/35) present in the unstructured N-terminal sequence of the protein. The cleavage of an abasic site located in a G4 structure by Ape1 depends on the DNA conformation or the position of the lesion and on electrostatic interactions between the protein and the nucleic acids. Moreover, Ape1 mutants mimicking the acetylated protein display increased cleavage activity for abasic sites. We found that nucleophosmin (NPM1), which binds the N-terminal sequence of Ape1, plays a role in modulating telomere length and Ape1 activity at abasic G4 structures. Thus, the Ape1 N-terminal sequence is an important relay site for regulating the enzyme's activity on G4-telomeric sequences, and specific acetylatable lysine residues constitute key regulatory sites of Ape1 enzymatic activity dynamics at telomeres
Faculty Opinions recommendation of Comet assay to measure DNA repair: approach and applications.
No full textFaculty Opinions recommendation of Two pathways for base excision repair in mammalian cells.
No full textFaculty Opinions recommendation of Studying the organization of DNA repair by single-cell and single-molecule imaging.
No full textAdaptive responses to genotoxic damage: Bacterial strategies to prevent ‐mutation and cell death
No full textEnzyme Structures: DNA repair flips out
No full textAbstractNew insights into the workings of the repair enzymes that police the genome for damage to DNA come from the recently determined structures of two uracil-DNA glycosylases
Faculty Opinions recommendation of Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis.
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