The repair of DNA double-strand breaks (DSBs) is essential to maintain genomic integrity. In higher eukaryotes, DNA DSBs are predominantly repaired by non-homologous end joining (NHEJ), but DNA ends can also be joined by an alternative error-prone mechanism termed microhomology-mediated end joining (MMEJ). In MMEJ, the repair of DNA breaks is mediated by annealing at regions of microhomology an...

The cyclin-dependent kinase inhibitor p21CDKN1A plays a fundamental role in the DNA-damage response by inducing cell-cycle arrest, and by inhibiting DNA replication through association with the proliferating cell nuclear antigen (PCNA). However, the role of such an interaction in DNA repair is poorly understood and controversial. Here, we provide evidence that a pool of p21 protein is rapidly r...

Recently it was observed that the DNA repair protein human O(6)-alkylguanine-DNA alkyltransferase repairs lesions at the 5' ends of 70-nucleotide single-stranded DNA roughly threefold more frequently than lesions at the 3' ends. Here, we introduce a coarse-grained model to show how a local asymmetry in binding kinetics (rather than thermodynamics) together with irreversible alkyl transfer can g...

PURPOSE The epidermal growth factor receptor (EGFR) is commonly expressed in human tumors and provides a target for therapy. Gefitinib (Iressa, ZD1839) is a quinazoline derivative that inhibits EGFR tyrosine kinase activity. Gefitinib demonstrated anticancer efficacy in vivo, and although experiments in vitro have suggested that inhibition of EGFR modulates the activity of chemotherapeutic agen...

Cells of higher eukaryotes process double strand breaks (DSBs) in their genome using a non-homologous end joining apparatus that utilizes DNA-PK and other well characterized factors (D-NHEJ). Cells with defects in D-NHEJ, repair the majority of DSBs using a slow-repair pathway which is independent of genes of the RAD52 epistasis group and functions as a backup (B-NHEJ). Recent studies implicate...

The anticancer agents 4'-demethylepipodophyllotoxin-4-(4,6-O-ethylidene-beta-D-glucopyra noside (etoposide) (VP16-213) and 4'-demethylepipodophyllotoxin-4-(4,6-O-thenylidene-beta-D-gl ucopyranoside (teniposide) (VM26) produce cytotoxicity by inhibiting type II topoisomerase, resulting in an accumulation of DNA breaks. By using alkaline elution techniques to assess in vivo DNA break frequencies,...

Reduced expression of the metastasis suppressor NM23-H1 is associated with aggressive forms of multiple cancers. Here, we establish that NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 30–50 exonuclease and nucleoside diphosphate kinase, are novel participants in the cellular response toUV radiation (UVR)–inducedDNAdamage. NM23-H1 deficiency ...

Oxidative DNA damage is the most frequent type of damage encountered by aerobic cells and may play an important role in biological processes such as mutagenesis, carcinogenesis and aging in humans. Oxidative damage generates a myriad of modifications in DNA. We investigated the cellular repair of DNA base damage products in DNA of cultured human lymphoblast cells, which were exposed to oxidativ...

In this study, the effect of DNA single strand breaks (ssb) on the neutral (pH 9.6) filter elution of DNA from Chinese hamster ovary (CHO K1) cells containing DNA double strand breaks (dsb) was investigated. Protein associated ssb were induced by the inhibition of DNA topoisomerase I with camptothecin (cpt). Protein associated dsb were introduced by treating cells with the DNA topoisomerase II ...

Mesenchymal stem cells (MSCs) are of interest for use in diverse cellular therapies. Ex vivo expansion of MSCs intended for transplantation must result in generation of cells that maintain fidelity of critical functions. Previous investigations have identified genetic and phenotypic alterations of MSCs with in vitro passage, but little is known regarding how culturing influences the ability of ...