Efficient DNA base excision repair in ataxia telangiectasia cells

Cappelli, Enrico; Rossi, Ottavio; Chessa, Luciana; Fròsina, Guido

doi:10.1046/j.1432-1033.2000.01789.x

Cited by 8 publications

(3 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Filling of the mtDNA gap is performed by DNA pol γ, and the repair patch is sealed by DNA Lig3 [15,16]. Interestingly, total cell lysates from A-T cells exhibited efficient BER activity because nuclear BER is functional [19]. Therefore, even though nuclear and mtBER share similar enzymes and pathways, our data suggest that ATM-deficient cells are less efficient at one or more of the BER steps that are specific to mtDNA repair.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia

et al. 2014

View full text Add to dashboard Cite

Ataxia telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria are reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3.

show abstract

Section: Resultsmentioning

confidence: 99%

Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia

et al. 2014

View full text Add to dashboard Cite

show abstract

“…BER in particular, has been poorly studied in A-T cells. To the best of our knowledge, a single study investigated BER in A-T lymphoblasts transformed with the Epstein-Barr virus, concluding that these cells bear normal BER capacity ( 43 ). However, we have recently shown that viral transformation alters BER coordination ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells

Poletto

Yang

Fletcher

et al. 2017

Nucleic Acids Research

View full text Add to dashboard Cite

Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function.

show abstract

“…It is believed that minor SSBs can be repaired independently of ATM and ATR using the BER pathway [ 133 ]. A targeted siRNA screen against DNA repair genes revealed that inhibition of several factors involved in the short-patch BER pathway impeded HIV-1 replication [ 134 ].…”

Section: Retroviral Integration and The Ddrmentioning

confidence: 99%

Activation of the DNA Damage Response by RNA Viruses

2016

View full text Add to dashboard Cite

RNA viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. Numerous viruses introduce DNA damage and genetic instability in host cells during their lifecycles and some species also manipulate components of the DNA damage response (DDR), a complex and sophisticated series of cellular pathways that have evolved to detect and repair DNA lesions. Activation and manipulation of the DDR by DNA viruses has been extensively studied. It is apparent, however, that many RNA viruses can also induce significant DNA damage, even in cases where viral replication takes place exclusively in the cytoplasm. DNA damage can contribute to the pathogenesis of RNA viruses through the triggering of apoptosis, stimulation of inflammatory immune responses and the introduction of deleterious mutations that can increase the risk of tumorigenesis. In addition, activation of DDR pathways can contribute positively to replication of viral RNA genomes. Elucidation of the interactions between RNA viruses and the DDR has provided important insights into modulation of host cell functions by these pathogens. This review summarises the current literature regarding activation and manipulation of the DDR by several medically important RNA viruses.

show abstract

Efficient DNA base excision repair in ataxia telangiectasia cells

Cited by 8 publications

References 37 publications

Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia

Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia

Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells

Activation of the DNA Damage Response by RNA Viruses

Contact Info

Product

Resources

About