To live or to die: a matter of processing damaged DNA termini in neurons

El‐Khamisy, Sherif F.

doi:10.1002/emmm.201000114

Cited by 45 publications

(50 citation statements)

References 113 publications

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“…Notably, accumulation of nuclear PDBs is pathogenic in a number of neurological disorders such as spinocerebellar ataxia with axonal neuropathy (SCAN1) and ataxia telangiectasia ( 14 ). Given the high metabolic activity and energy demand of cells in the nervous system, the data reported here suggest that accumulation of mitochondrial PDBs may also be pathogenic, disrupting mitochondrial gene transcription and bioenergetics, thereby causing progressive neuronal demise.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

et al. 2017

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“…Although TDP1 is a well-established pathway for the excision of trapped Top1 cleavage complexes [40, 41], it is clear from studies performed in yeast [2, 31] and human cells [42–44] that alternative endonuclease pathways including XPF-ERCC1 and Mus81 are critical to for removing by endonucleolytic cleavage of the 3’-DNA segment covalently attached to Top1. In addition, both HOP_62 and H522 cells express TDP2 protein, which might be compensatory given its reported role in resolving Top1cc in the absence of TDP1 [28, 45] (Fig.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel

et al. 2014

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Tyrosyl-DNA-phosphodiesterase 1 (TDP1) repairs 3’-blocking DNA lesions by catalytically hydrolyzing the tyrosyl-DNA-phosphodiester bond of trapped topoisomerase I (Top1) cleavage complexes (Top1cc). It also removes 3’-blocking residues derived from oxidative damage or incorporation of chain terminating anticancer and antiviral nucleosides. Thus, TDP1 is regarded as a determinant of resistance to Top1 inhibitors and chain terminating nucleosides, and possibly of genomic stability. In the 60 cell lines of the NCI Developmental Therapeutic Anticancer Screen (the NCI-60), whose whole genome transcriptome and mutations have recently been characterized, we discovered two human lung cancer cell lines deficient for TDP1 (NCI_H522 and HOP_62). HOP_62 shows undetectable TDP1 mRNA and NCI_H522 bears a homozygous deleterious mutation of TDP1 at a highly conserved amino acid residue (K292E). Absence of TDP1 protein and lack of TDP1 catalytic activity were demonstrated in cell lysates from both cell lines. Lack of TDP1 expression in HOP_62 was shown to be due to TDP1 promoter hypermethylation. Our study provides insights into the possible inactivation of TDP1 in cancers and its relationship to cellular response to Top1-targeted drugs. It also reveals two TDP1 knockout lung cancer cell lines for further TDP1 functional analyses.

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“…These 5′-adenylated BER intermediates with 3′-modified or unnatural bases could potentially become cytotoxic and lead to abnormal DNA replication and double-strand breaks. Therefore, repair of the 5′-adenylated BER intermediates by DNA-end processing enzymes is critical to cell viability and genomic stability [35, 51]. …”

Section: Impact Of Pol β Structural Conformations On Channeling Dnmentioning

confidence: 99%

Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair

Çağlayan¹,

Wilson²

2015

DNA Repair

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DNA lesions arise from many endogenous and environmental agents, and they promote deleterious events leading to genomic instability and cell death. Base excision repair (BER) is the main DNA repair pathway responsible for repairing single strand breaks, base lesions and abasic sites in mammalian cells. During BER, DNA substrates and repair intermediates are channeled from one step to the next in a sequential fashion so that release of toxic repair intermediates is minimized. This includes handoff of the product of gap-filling DNA synthesis to the DNA ligation step. The conformational differences in DNA polymerase β (pol β) associated with incorrect or oxidized nucleotide (8-oxodGMP) insertion could impact channeling of the repair intermediate to the final step of BER, i.e., DNA ligation by DNA ligase I or the DNA Ligase III/XRCC1 complex. Thus, modified DNA ligase substrates produced by faulty pol β gap-filling could impair coordination between pol β and DNA ligase. Ligation failure is associated with 5′-AMP addition to the repair intermediate and accumulation of strand breaks that could be more toxic than the initial DNA lesions. Here, we provide an overview of the consequences of ligation failure in the last step of BER. We also discuss DNA-end processing mechanisms that could play roles in reversal of impaired BER.

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To live or to die: a matter of processing damaged DNA termini in neurons

Cited by 45 publications

References 113 publications

Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel

Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair

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