Cadmium treatment suppresses DNA polymerase δ catalytic subunit gene expression by acting on the p53 and Sp1 regulatory axis

Antoniali, Giulia; Marcuzzi, Federica; Casarano, Elena; Tell, Gianluca

doi:10.1016/j.dnarep.2015.08.007

Cited by 26 publications

(16 citation statements)

References 61 publications

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“…Al ions, together with amyloid peptide alters DNA conformation and super helicity [178]. Further, elevated levels of Fe, Cu, Zn inhibit the proteins of BER pathway via changes in protein conformation and cysteine oxidation [134, 179], whereas excess Pb, Fe, Cd cause inhibition of APE1’s nuclease activity, and exposure to Cd also inhibits OGG1 activity, and down-regulates DNA polymerase δ (Polδ) expression, thereby, impairing BER pathway [180]. Furthermore, during pathological conditions like ischemic stroke, oxidative stress activates nuclear metal-dependent proteases leading to nuclear proteolysis of ATM, XRCC1, and PARP1, and thereby affecting repair.…”

Section: Dna Repair Defects and Neuronal Phenotypesmentioning

confidence: 99%

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Weng

Dharmalingam

Vasquez

et al. 2017

Mechanisms of Ageing and Development

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A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

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Section: Dna Repair Defects and Neuronal Phenotypesmentioning

confidence: 99%

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Weng

Dharmalingam

Vasquez

et al. 2017

Mechanisms of Ageing and Development

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“…The interaction between Sp1 and p53 has been previously described ( 28 , 32 ). As the p53/Sp1 association has been shown to increase upon DNA damage ( 29 , 33 ) it is possible to speculate that, in the absence of XRCC1, Sp1 stability might be indeed negatively affected via interaction with p53. p53 itself is known to be controlled by several post-translational modifications, including phosphorylation by the ataxia-telangiectasia mutated (ATM) protein kinase.…”

Section: Discussionmentioning

confidence: 99%

p53 coordinates base excision repair to prevent genomic instability

et al. 2016

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DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells.

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“…Cd is confirmed to induce mitochondria damage followed by energy metabolism abnormality which leads to DNA damage, cell apoptosis and senescence through activation of p53 and p21 [42][43][44][45]. We detected the DNA damage and repair markers, γH2ax and BRCA1, Cd treatment significantly increased the fluorescent intensity of γH2ax and BRCA1 in cell nucleus (Figure 6A,B).…”

Section: Histological and Immunostainingmentioning

confidence: 95%

Ex vivo detection of cadmium‐induced renal damage by using confocal Raman spectroscopy

Shen

et al. 2019

Journal of Biophotonics

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Cadmium (Cd) is a toxic heavy metal which is harmful to environment and organisms. The reabsorption of Cd in kidney leads it to be the main damaged organ in animals under the Cd exposure. In this work, we applied confocal Raman spectroscopy to map the pathological changes in situ in normal and Cd‐exposed mice kidney. The renal tissue from Cd‐exposed group displayed a remarkable decreasing in the intensity of typical peaks related to mitochondria, DNA, proteins and lipids. On the contrary, the peaks of collagen in Cd‐exposed group elevated significantly. The components in each tissue were identified and distinguished by principal component analysis. Furthermore, all the biological investigations in this study were consistent with the Raman spectrum detection, which revealed the progression and degree of lesion induced by Cd. The confocal Raman spectroscopy provides a new perspective for in situ monitoring of substances changes in tissues, which exhibits more comprehensive understanding of the pathogenic mechanisms of heavy metals in molecular toxicology.

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Cadmium treatment suppresses DNA polymerase δ catalytic subunit gene expression by acting on the p53 and Sp1 regulatory axis

Cited by 26 publications

References 61 publications

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

p53 coordinates base excision repair to prevent genomic instability

Ex vivo detection of cadmium‐induced renal damage by using confocal Raman spectroscopy

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