Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
DNA Repair (Amst)
2014 Jan 01;13:22-31. doi: 10.1016/j.dnarep.2013.11.002.
Show Gene links
Show Anatomy links
Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.
Sharma NK
,
Lebedeva M
,
Thomas T
,
Kovalenko OA
,
Stumpf JD
,
Shadel GS
,
Santos JH
.
???displayArticle.abstract???
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 is 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.
Alexander,
ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS.
2010, Pubmed
Alexander,
ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS.
2010,
Pubmed
Ambrose,
Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions.
2013,
Pubmed
Ambrose,
Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells.
2007,
Pubmed
Arakawa,
Functional redundancy between DNA ligases I and III in DNA replication in vertebrate cells.
2012,
Pubmed
,
Xenbase
Cappelli,
Efficient DNA base excision repair in ataxia telangiectasia cells.
2000,
Pubmed
Chen,
Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair.
2008,
Pubmed
Cosentino,
ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair.
2011,
Pubmed
,
Xenbase
D'Souza,
Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia-telangiectasia.
2013,
Pubmed
Dong,
ATM mediates oxidative stress-induced dephosphorylation of DNA ligase IIIalpha.
2006,
Pubmed
,
Xenbase
Eaton,
Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis.
2007,
Pubmed
Fletcher,
Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.
2010,
Pubmed
Frezza,
Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts.
2007,
Pubmed
Gao,
DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair.
2011,
Pubmed
,
Xenbase
Guo,
ATM activation in the presence of oxidative stress.
2010,
Pubmed
Guo,
ATM activation by oxidative stress.
2010,
Pubmed
Jenkins,
p53 N-terminal phosphorylation: a defining layer of complex regulation.
2012,
Pubmed
Johri,
Mitochondrial dysfunction in neurodegenerative diseases.
2012,
Pubmed
Kamsler,
Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice.
2001,
Pubmed
Lakshmipathy,
Antisense-mediated decrease in DNA ligase III expression results in reduced mitochondrial DNA integrity.
2001,
Pubmed
,
Xenbase
Lakshmipathy,
Double strand break rejoining by mammalian mitochondrial extracts.
1999,
Pubmed
Lu,
Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease.
2013,
Pubmed
Mandavilli,
Mitochondrial DNA repair and aging.
2002,
Pubmed
Oliveira,
Genetic polymorphisms and cervical cancer development: ATM G5557A and p53bp1 C1236G.
2012,
Pubmed
Palii,
Dissecting cellular responses to irradiation via targeted disruptions of the ATM-CHK1-PP2A circuit.
2013,
Pubmed
Parsons,
CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins.
2008,
Pubmed
,
Xenbase
Patel,
Ataxia telangiectasia mutated influences cytochrome c oxidase activity.
2011,
Pubmed
Pontarin,
Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells.
2012,
Pubmed
Santos,
Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death.
2003,
Pubmed
Santos,
Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells.
2006,
Pubmed
Schmidt,
Mitochondrial protein import: from proteomics to functional mechanisms.
2010,
Pubmed
Sharma,
Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.
2014,
Pubmed
Sharma,
Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria.
2012,
Pubmed
Shen,
Association between ATM polymorphisms and cancer risk: a meta-analysis.
2012,
Pubmed
Shiloh,
The ATM protein kinase: regulating the cellular response to genotoxic stress, and more.
2013,
Pubmed
Shokolenko,
Mitochondrial DNA ligase is dispensable for the viability of cultured cells but essential for mtDNA maintenance.
2013,
Pubmed
,
Xenbase
Simsek,
Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair.
2011,
Pubmed
,
Xenbase
Skowronska,
ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele.
2012,
Pubmed
Sykora,
Repair of persistent strand breaks in the mitochondrial genome.
2012,
Pubmed
Tann,
Apoptosis induced by persistent single-strand breaks in mitochondrial genome: critical role of EXOG (5'-EXO/endonuclease) in their repair.
2011,
Pubmed
Vafai,
Mitochondrial disorders as windows into an ancient organelle.
2012,
Pubmed
Valentin-Vega,
Mitochondrial dysfunction in ataxia-telangiectasia.
2012,
Pubmed
Van Houten,
Role of mitochondrial DNA in toxic responses to oxidative stress.
2006,
Pubmed
Wang,
Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase.
2004,
Pubmed
Zheng,
Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates.
2008,
Pubmed
