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Werner syndrome (WS) is the hallmark premature aging syndrome in which the patients appear much older than their actual chronological age. The disorder is associated with significantly increased genome instability and with transcriptional deficiencies. There has been some uncertainty about whether WS cells are defective in DNA repair. We thus examined(More)
The base excision repair (BER) pathway is essential for the removal of DNA bases damaged by alkylation or oxidation. A key step in BER is the processing of an apurinic/apyrimidinic (AP) site intermediate by an AP endonuclease. The major AP endonuclease in human cells (APE1, also termed HAP1 and Ref-1) accounts for >95% of the total AP endonuclease activity,(More)
Werner Syndrome is a premature aging disorder characterized by genomic instability, elevated recombination, and replication defects. It has been hypothesized that defective processing of certain replication fork structures by WRN may contribute to genomic instability. Fluorescence resonance energy transfer (FRET) analyses show that WRN and Flap(More)
Base excision repair (BER) is the major pathway for processing of simple lesions in DNA, including single-strand breaks, base damage, and base loss. The scaffold protein XRCC1, DNA polymerase beta, and DNA ligase IIIalpha play pivotal roles in BER. Although all these enzymes are essential for development, their cellular levels must be tightly regulated(More)
Cellular DNA repair is a frontline system that is responsible for maintaining genome integrity and thus preventing premature aging and cancer by repairing DNA lesions and strand breaks caused by endogenous and exogenous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer(More)
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(More)
Converting lead compounds into drug candidates is a crucial step in drug development, requiring early assessment of potency, selectivity, and off-target effects. We have utilized activity-based chemical proteomics to determine the potency and selectivity of deubiquitylating enzyme (DUB) inhibitors in cell culture models. Importantly, we characterized the(More)
Base excision repair (BER) is a major DNA repair pathway employed in mammalian cells that is required to maintain genome stability, thus preventing several human diseases, such as ageing, neurodegenerative diseases and cancer. This is achieved through the repair of damaged DNA bases, sites of base loss and single strand breaks of varying complexity that are(More)
The hereditary disease Cockayne syndrome (CS) is a complex clinical syndrome characterized by arrested post-natal growth as well as neurological and other defects. The CSA and CSB genes are implicated in this disease. The clinical features of CS can also accompany the excision repair-defective hereditary disorder xeroderma pigmentosum (XP) from genetic(More)
The role of closely spaced lesions on both DNA strands in the induction of double-strand breaks and formation of deletions was studied. For this purpose a polylinker sequence flanked by 165 bp direct repeats was inserted within the tet gene of pBR327. This plasmid was used to construct DNA containing one or two uracil residues which replaced cytosine(More)