Overexpression of DNA ligase III in mitochondria protects cells against oxidative stress and improves mitochondrial DNA base excision repair

Akbari, Mansour; Keijzers, Guido; Maynard, Scott; Scheibye‐Knudsen, Morten; Desler, Claus; Hickson, Ian D.; Bohr, Vilhelm A.

doi:10.1016/j.dnarep.2014.01.015

Cited by 38 publications

(36 citation statements)

References 68 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reduced levels and activity of LIGIII have been detected in major human neurodegenerative diseases including ataxia telangiectasia (in ATM patient cells and ATM-KO mice) (Sharma et al 2014) and Alzheimer’s disease (Canugovi et al 2013, 2014). LIGIII activity has been reported to be the rate-limiting step of BER in mitochondria (Akbari et al 2014). Thus, regulation of this step should be the best target for stimulation of mitochondrial BER.…”

Section: Bermentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye‐Knudsen

et al. 2015

Cold Spring Harb Perspect Med

Self Cite

316

197

View full text Add to dashboard Cite

Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.

show abstract

Section: Bermentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye‐Knudsen

et al. 2015

Cold Spring Harb Perspect Med

Self Cite

316

197

View full text Add to dashboard Cite

show abstract

“…ATM deficiency downregulates Lig III and lowers BER capacity in the mitochondria [78]. Lig III is the only DNA ligase in mitochondria and is the rate-limiting enzyme in mtBER[79]. These observations suggest a mitochondrial defect in A-T cells and additional studies of mitochondrial function in A-T is warranted.…”

Section: Introductionmentioning

confidence: 99%

The role of DNA base excision repair in brain homeostasis and disease

et al. 2015

Self Cite

View full text Add to dashboard Cite

Chemical modification and spontaneous loss of nucleotide bases from DNA are estimated to occur at the rate of thousands per human cell per day. DNA base excision repair (BER) is a critical mechanism for repairing such lesions in nuclear and mitochondrial DNA. Defective expression or function of proteins required for BER or proteins that regulate BER have been consistently associated with neurological dysfunction and disease in humans. Recent studies suggest that DNA lesions in the nuclear and mitochondrial compartments and the cellular response to those lesions have a profound effect on cellular energy homeostasis, mitochondrial function and cellular bioenergetics, with especially strong influence on neurological function. Further studies in this area could lead to novel approaches to prevent and treat human neurodegenerative disease.

show abstract

“…However, there is only a limited difference in the amount of repair product (upper band), suggesting the rate-limiting step is not nucleotide incorporation. Previous research has reported that ligation activity is rate limiting in BER using this assay (33). The comparable ligation activity can be seen as indirect evidence that the samples have equal input protein concentration.…”

Section: Resultsmentioning

confidence: 71%

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Sýkora

Kanno

Akbari

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

We have detected DNA polymerase beta (Pol␤), known as a key nuclear base excision repair (BER) protein, in mitochondrial protein extracts derived from mammalian tissue and cells. Manipulation of the N-terminal sequence affected the amount of Pol␤ in the mitochondria. Using Pol␤ fragments, mitochondrion-specific protein partners were identified, with the interactors functioning mainly in DNA maintenance and mitochondrial import. Of particular interest was the identification of the proteins TWINKLE, SSBP1, and TFAM, all of which are mitochondrion-specific DNA effectors and are known to function in the nucleoid. Pol␤ directly interacted functionally with the mitochondrial helicase TWINKLE. Human kidney cells with Pol␤ knockout (KO) had higher endogenous mitochondrial DNA (mtDNA) damage. Mitochondrial extracts derived from heterozygous Pol␤ mouse tissue and KO cells had lower nucleotide incorporation activity. Mouse-derived Pol␤ null fibroblasts had severely affected metabolic parameters. Indeed, gene knockout of Pol␤ caused mitochondrial dysfunction, including reduced membrane potential and mitochondrial content. We show that Pol␤ is a mitochondrial polymerase involved in mtDNA maintenance and is required for mitochondrial homeostasis.KEYWORDS DNA polymerase beta, mitochondrial DNA repair, TFAM, base excision repair, mitochondria, mitochondrial health, mutational studies C ellular DNA repair is critical for genomic stability, and the accumulation of DNA damage has been linked to many debilitating human disorders, including accelerated aging, cancer, and neurodegeneration (reviewed in references 1 and 2). Mammalian cells have two genomes, nuclear and mitochondrial, and both have the ability to replicate, accumulate DNA damage, and propagate mutations. The nucleus contains the vast majority of the mammalian genome and has extensive ability to repair complex bulky adducts, double-strand breaks (DSB), single-strand breaks (SSB), and hundreds of chemical DNA modifications. The ability to effectively repair this breadth of damage is achieved through multiple, often overlapping, DNA repair pathways. In contrast, the repair of mitochondrial DNA (mtDNA) is a more limited version of nuclear DNA (nDNA) repair. Mitochondria lack nucleotide excision repair, and the presence of double-strand break repair is debated (recently reviewed in reference 3). Despite the mitochondria having attenuated DNA repair capabilities compared to the nucleus, the accumulation of mtDNA damage is not without consequence. Ineffective mtDNA maintenance is the underlying cause of many human diseases, including Alpers syndrome and chronic progressive external ophthalmoplegia (CPEO) caused by mutations in mitochondrial polymerase gamma (Pol␥) or the TWINKLE helicase (4-6). The accu-

show abstract

Overexpression of DNA ligase III in mitochondria protects cells against oxidative stress and improves mitochondrial DNA base excision repair

Cited by 38 publications

References 68 publications

DNA Damage, DNA Repair, Aging, and Neurodegeneration

DNA Damage, DNA Repair, Aging, and Neurodegeneration

The role of DNA base excision repair in brain homeostasis and disease

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Contact Info

Product

Resources

About