DNA double strand break repair in brain: Reduced NHEJ activity in aging rat neurons

Vyjayanti, Vaddadi N.; Rao, K. S.

doi:10.1016/j.neulet.2005.09.053

Cited by 81 publications

(61 citation statements)

References 22 publications

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“…By correlation, Ku levels decline and their cellular distribution is altered as human fibroblasts approach senescence (Seluanov et al, 2007b). In keeping with these results, NHEJ function declines in the brains of aging rats (Ren and de Ortiz, 2002;Vyjayanti and Rao, 2006) and in Alzheimer's patients (Shackelford, 2006) and becomes less efficient and more error-prone in senescent cells (Seluanov et al, 2004). Thus, NHEJ declines with age supporting the possibility that defective NHEJ will lead to early aging.…”

Section: Pathways That Repair or Suppress Dna Dsbsmentioning

confidence: 66%

DNA double-strand breaks: A potential causative factor for mammalian aging?

Han

Mitchell

Hasty

2008

Mechanisms of Ageing and Development

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Aging is a pleiotropic and stochastic process influenced by both genetics and environment. As a result the fundamental underlying causes of aging are controversial and likely diverse. Genome maintenance and in particular the repair of DNA damage is critical to ensure longevity needed for reproduction and as a consequence imperfections or defects in maintaining the genome may contribute to aging. There are many forms of DNA damage with double-strand breaks (DSBs) being the most toxic. Here we discuss DNA DSBs as a potential causative factor for aging including factors that generate DNA DSBs, pathways that repair DNA DSBs, consequences of faulty or failed DSB repair and how these consequences may lead to age-dependent decline in fitness. At the end we compare mouse models of premature aging that are defective for repairing either DSBs or UV lightinduced lesions. Based on these comparisons we believe the basic mechanisms responsible for their aging phenotypes are fundamentally different demonstrating the complex and pleiotropic nature of this process.

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Section: Pathways That Repair or Suppress Dna Dsbsmentioning

confidence: 66%

DNA double-strand breaks: A potential causative factor for mammalian aging?

Han

Mitchell

Hasty

2008

Mechanisms of Ageing and Development

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“…3,4,6,11,17,23 Relevant research in humans was mainly focused on age-related change in the recruitment kinetics of essential DNA damage response factors, assayed by immune-staining; 26 age-related change of genomic instability,…”

Section: Discussionmentioning

confidence: 99%

“…Using different analysis approaches, several studies have demonstrated that aging is often associated with the accumulation of DNA DSBs in various organs and tissues in mammals such as mice and humans. [7][8][9][10][11] Moreover, a recent study provides direct evidence that an induction of DNA DSBs in genomes causes aging in mouse livers. 12 However, why DNA DSBs accumulate with age remains an open question.…”

mentioning

confidence: 99%

“…A number of studies indicate that it may be a consequence of a progressing imbalance between DNA damage and the efficiency of the molecular machinery that catalyzes DNA repair. 7,9,11 Two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) evolved to repair DNA DSBs. NHEJ is further divided into two sub-pathways: the classical NHEJ pathway (c-NHEJ)-in which the major participating factors include DNA-PKcs, Ku70/Ku80 heterodimers, Artemis, XRCC4, XLF and DNA Lig4-and the alternative NHEJ pathway (alt-NHEJ), comprised of the repair factors, PARP1 and DNA Lig3.…”

mentioning

confidence: 99%

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Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Zhang

Chen

et al. 2016

Cell Death Differ

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Failing to repair DNA double-strand breaks by either nonhomologous end joining (NHEJ) or homologous recombination (HR) poses a threat to genome integrity, and may have roles in the onset of aging and age-related diseases. Recent work indicates an age-related decrease of NHEJ efficiency in mouse models, but whether NHEJ and HR change with age in humans and the underlying mechanisms of such a change remain uncharacterized. Here, using 50 eyelid fibroblast cell lines isolated from healthy donors at the age of 16-75 years, we demonstrate that the efficiency and fidelity of NHEJ, and the efficiency of HR decline with age, leading to increased IR sensitivity in cells isolated from old donors. Mechanistic analysis suggests that decreased expression of XRCC4, Lig4 and Lig3 drives the observed, age-associated decline of NHEJ efficiency and fidelity. Restoration of XRCC4 and Lig4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts. In contrast, essential HR-related factors, such as Rad51, do not change in expression level with age, but Rad51 exhibits a slow kinetics of recruitment to DNA damage sites in aged fibroblasts. Further rescue experiments indicate that restoration of XRCC4 and Lig4 may suppress the onset of stress-induced premature cellular senescence, suggesting that improving NHEJ efficiency and fidelity by targeting the NHEJ pathway holds great potential to delay aging and mitigate aging-related pathologies. Cell Death and Differentiation (2016) 23, 1765-1777; doi:10.1038/cdd.2016.65; published online 8 July 2016Aging in mammals is a complex biological process, characterized by several major hallmarks.1,2 Of all the features associated with aging, a gradual destabilization of genome integrity is perhaps the most fundamental as increased genomic instability may lead to other age-associated phenotypes such as cellular senescence and stem cell exhaustion. Indeed, for the past several decades, numerous studies have indicated that DNA mutations and chromosomal rearrangements gradually accumulate with age.3-6 Of all types of DNA lesions, which may contribute to the gradual loss of genetic information during aging, DNA double-strand breaks (DSBs) are the most hazardous to cells as unrepaired or inappropriately repaired DSBs can cause insertions, deletions and chromosomal rearrangements. Using different analysis approaches, several studies have demonstrated that aging is often associated with the accumulation of DNA DSBs in various organs and tissues in mammals such as mice and humans. [7][8][9][10][11] Moreover, a recent study provides direct evidence that an induction of DNA DSBs in genomes causes aging in mouse livers.12 However, why DNA DSBs accumulate with age remains an open question. A number of studies indicate that it may be a consequence of a progressing imbalance between DNA damage and the efficiency of the molecular machinery that catalyzes DNA repair. 7,9,11 Two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) evolved to repair DNA DSBs. NHEJ is...

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“…In the context of aging, the steady-state levels of DNA DSBs have been shown to increase with age [9,10]. Furthermore, the improper repair of DSBs can lead to large scale genomic sequence rearrangements, such as translocations, insertions, and deletions [11], and an increased frequency of such rearrangements is often observed in aged cells [12][13][14][15][16]. Consistent with these findings, it has also been shown that deficiencies in the ability to repair DSBs cause accelerated aging [17].…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific differences in the accumulation of sequence rearrangements with age

et al. 2008

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Mitotic homologous recombination (HR) is a critical pathway for the accurate repair of DNA double strand breaks (DSBs) and broken replication forks. While generally error-free, HR can occur between misaligned sequences, resulting in deleterious sequence rearrangements that can contribute to cancer and aging. To learn more about the extent to which HR occurs in different tissues during the aging process, we used Fluorescent Yellow Direct Repeat (FYDR) mice in which an HR event in a transgene yields a fluorescent phenotype. Here, we show tissue-specific differences in the accumulation of recombinant cells with age. Unlike pancreas, which shows a dramatic 23-fold increase in recombinant cell frequency with age, skin shows no increase in vivo. In vitro studies indicate that juvenile and aged primary fibroblasts are similarly able to undergo HR in response to endogenous and exogenous DNA damage. Therefore, the lack of recombinant cell accumulation in the skin is most likely not due to an inability to undergo de novo HR events. We propose that tissue-specific differences in the accumulation of recombinant cells with age result from differences in the ability of recombinant cells to persist and clonally expand within tissues.

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DNA double strand break repair in brain: Reduced NHEJ activity in aging rat neurons

Cited by 81 publications

References 22 publications

DNA double-strand breaks: A potential causative factor for mammalian aging?

DNA double-strand breaks: A potential causative factor for mammalian aging?

Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

Tissue-specific differences in the accumulation of sequence rearrangements with age

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