Cadmium and copper inhibit both DNA repair activities of polynucleotide kinase

Whiteside, James R.; Box, Clare L; McMillan, Trevor J.; Allinson, Sarah L.

doi:10.1016/j.dnarep.2009.11.004

Cited by 34 publications

(22 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet single-nucleotide insertion has been observed in in vitro repair reactions utilizing PNKP substrates and human whole cell extracts [56]. To determine if pol β has a repair role under conditions of functional PNKP deficiency, pol β was knocked down by lentivirus in the XCKD16 cell line.…”

Section: Resultsmentioning

confidence: 99%

“…S6A and B). Only minor CPT hypersensitivity is observed in pol β null cells and the hypersensitivity is not increased in Xrcc1 −/− MEFs with a knock down of pol β [30], but single-nucleotide insertion has been reported in vitro when using PNKP substrates [56]. Pol β was knocked down in XCKD16 cells to identify any back-up role for pol β-dependent repair under conditions of PNKP functional deficiency.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

XRCC1-mediated repair of strand breaks independent of PNKP binding

et al. 2017

View full text Add to dashboard Cite

Repair of DNA-protein crosslinks and oxidatively damaged DNA base lesions generates intermediates with nicks or gaps with abnormal and blocked 3′-phosphate and 5′-OH ends that prevent the activity of DNA polymerases and ligases. End cleaning in mammalian cells by Tdp1 and PNKP produces the conventional 3′-OH and 5′-phosphate DNA ends suitable for completion of repair. This repair function of PNKP is facilitated by its binding to the scaffold protein XRCC1, and phosphorylation of XRCC1 by CK2 at several consensus sites enables PNKP binding and recruitment to DNA damage. To evaluate this documented repair process, a phosphorylation mutant of XRCC1, designed to eliminate PNKP binding, was stably expressed in Xrcc1−/− mouse fibroblast cells. Analysis of PNKP-GFP accumulation at micro-irradiation induced damage confirmed that the XRCC1 phosphorylation mutant failed to support efficient PNKP recruitment, whereas there was rapid recruitment in cells expressing wild-type XRCC1. Recruitment of additional fluorescently-tagged repair factors PARP-1-YFP, GFF-XRCC1, PNKP-GFP and Tdp1-GFP to micro-irradiation induced damage was assessed in wild-type XRCC1-expressing cells. PARP-1-YFP recruitment was best fit to two exponentials, whereas kinetics for the other proteins were fit to a single exponential. The similar half-times of recruitment suggest that XRCC1 may be recruited with other proteins possibly as a pre-formed complex. Xrcc1−/− cells are hypersensitive to the DNA-protein cross-link inducing agent camptothecin (CPT) and the DNA oxidative agent H2O2 due in part to compromised PNKP-mediated repair. However, cells expressing the PNKP interaction mutant of XRCC1 demonstrated marked reversal of CPT hypersensitivity. This reversal represents XRCC1-dependent repair in the absence of the phosphorylation-dependent PNKP recruitment and suggests either an XRCC1-independent mechanism of PNKP recruitment or a functional back-up pathway for cleaning of blocked DNA ends.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

XRCC1-mediated repair of strand breaks independent of PNKP binding

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Whiteside et al, showed that Cd and Cu inhibit both phosphatase and kinase activities of PNKP with human cell extracts and recombinant protein [126]. Heavy metals could delay SSB rejoining in mammalian cells [127, 128].…”

Section: Ber/ssbr Inhibition By Pro-oxidant Metals: a Case Of Double mentioning

confidence: 99%

Oxidative Genome Damage and its Repair in Neurodegenerative Diseases: Function of Transition Metals as a Double-Edged Sword

Hegde

Rao

et al. 2011

JAD

View full text Add to dashboard Cite

The neurons in the central nervous system (CNS) with high O2 consumption and prolonged life span are chronically exposed to high levels of reactive oxygen species (ROS). Accumulation of ROS-induced genome damage in the form of oxidized bases and single-strand breaks (SSBs) as well as their defective or reduced repair in the brain has been implicated in the etiology of various neurological disorders including Alzheimer’s/Parkinson’s diseases (AD/PD). Although inactivating mutations in some DNA repair genes have been linked to hereditary neurodegenerative diseases, the underlying mechanisms of repair deficiencies for the sporadic diseases is not understood. The ROS-induced DNA damages are predominantly repaired via highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that transition metals iron (Fe) and copper (Cu) which accumulate excessively in the brains of AD, PD and other neurodegenerative diseases, act as a ‘double-edged sword’ by inducing genotoxic ROS and inhibiting DNA damage repair at the same time. These metals inhibit the base excision activity of NEIL family DNA glycosylases by oxidizing them, changing their structure, and inhibiting their binding to downstream repair proteins. Metal chelators and reducing agents partially reverse the inhibition, while curcumin with both chelating and reducing activities reverses the inhibition nearly completely. In this review, we have discussed the possible etiological linkage of BER/SSBR defects to neurodegenerative diseases and therapeutic potential of metal chelators in restoring DNA repair capacity.

show abstract

“…Through fenton chemistry, heavy metals may contribute independently and in conjunction with UV (particularly UVA) to free radical formation in melanocytes; the interaction between UV and heavy metals is a field of intensive investigation (Meyskens and Yang, 2011). There is also great interest in determining whether heavy metals may influence the ability of melanocytes to recover/repair UV-mediated DNA damage (Beyersmann and Hartwig, 2008;Joseph, 2009;Whiteside et al, 2010).…”

Section: Heavy Metal Exposurementioning

confidence: 99%