The DNA damage response: Balancing the scale between cancer and ageing

Seviour, Elena G.; Lin, Shiaw Yih

doi:10.18632/aging.100248

Cited by 55 publications

(43 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18,28,29 The 'comet assay' has been used extensively as a sensitive measurement of DNA damage in cells. 30,31 Therefore, we next performed the comet assay to detect any nuclear DNA lesions induced by chronic stress, especially in Leydig cells.…”

Section: Chronic Stress Promotes Lipofuscin Deposition In Leydig Cellsmentioning

confidence: 99%

“…[15][16][17] DNA is particularly susceptible to be damaged by ROS or other stresses, such as ionizing radiation and ultraviolet light; if effective repair mechanisms fail or are absent, the accumulation of DNA damage can trigger genomic instability and cellular senescence. 18 To confirm the hypothesis that chronic stress may accelerate the ageing process in Leydig cells and to examine the mechanisms underlying stress-induced ageing in Leydig cells, adult male Brown Norway (BN) rats were subjected to chronic unpredictable stress. Rat Leydig cells were then assessed for morphological alterations and lipofuscin accumulation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Wang¹,

Wang²,

Chen³

et al. 2012

Asian J Androl

View full text Add to dashboard Cite

Several studies have suggested that stress and ageing exert inhibitory effects on rat Leydig cells. In a pattern similar to the normal process of Leydig cell ageing, stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression that then results in decreased testosterone secretion. We hypothesized that chronic stress accelerates the degenerative changes associated with ageing in Leydig cells. To test this hypothesis, we established a model of chronic stress to evaluate stress-induced morphological and functional alterations in Brown Norway rat Leydig cells; additionally, intracellular lipofuscin levels, reactive oxygen species (ROS) levels and DNA damage were assessed. The results showed that chronic stress accelerated ageing-related changes: ultrastructural alterations associated with ageing, cellular lipofuscin accumulation, increased ROS levels and more extensive DNA damage were observed. Additionally, testosterone levels were decreased. This study sheds new light on the idea that chronic stress contributes to the degenerative changes associated with ageing in rat Leydig cells in vivo.

show abstract

Section: Chronic Stress Promotes Lipofuscin Deposition In Leydig Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Wang¹,

Wang²,

Chen³

et al. 2012

Asian J Androl

View full text Add to dashboard Cite

show abstract

“…The genome repair pathways also communicate with processes involved in induction of senescence and apoptosis when the damage cannot be repaired. Carefully balanced signalling cascades and regulatory systems are implicated in the maintenance of healthy cell survival in order to unfavour tumorigenesis and maintain stem and progenitor cells for renewal (anti-ageing) (Seviour & Lin 2010). Therefore, an effectively repaired genome is crucial not only for cancer prevention but also for lifespan extension.…”

Section: Consequences Of Genomic Instabilitymentioning

confidence: 99%

“…This has been shown in a mouse model to result from an accumulation of neurons harboring genomic damage, due to the inability of the mutant ATM protein to stimulate the p53 apoptotic cascade. Chk2 has also been shown to regulate apoptosis in a p53-dependent manner in vitro and in vivo in response to DNA damage (Seviour & Lin, 2010). Notably, the major recombinase of HR, Rad51, seems also to interact with p53, possibly serving as a tool for monitoring the extension as well the effectiveness of DNA repair processes (Henning & Sturzbecher Toxicology, 2003;Morita et al, 2010).…”

Section: Apoptosis and Dna Damagementioning

confidence: 99%

Structure-Function Relationship of DNA Repair Proteins: Lessons from BRCA1 and RAD51 Studies

Boutou¹,

Pappa²,

Stuerzbecher³

et al. 2011

DNA Repair

View full text Add to dashboard Cite

“…Failure to stabilize stalled forks can lead to replisome dissociation and fork degradation or collapse. DNA damage response (DDR) pathways maintain genomic integrity by rectifying or protecting stalled or collapsed forks and regulating DNA repair (9)(10)(11). In humans, accumulation of the ssDNA-binding protein Replication Protein A (RPA) at stalled forks signals recruitment of the S-phase checkpoint kinase ATR (12)(13)(14)(15), consequently triggering recruitment of proteins that promote sister chromatid cohesion and stabilize the histone/chromatin structure (16).…”

mentioning

confidence: 99%

A structure-specific nucleic acid-binding domain conserved among DNA repair proteins

Mason

Rambo

Greer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

SMARCAL1, a DNA remodeling protein fundamental to genome integrity during replication, is the only gene associated with the developmental disorder Schimke immuno-osseous dysplasia (SIOD). SMARCAL1-deficient cells show collapsed replication forks, S-phase cell cycle arrest, increased chromosomal breaks, hypersensitivity to genotoxic agents, and chromosomal instability. The SMARCAL1 catalytic domain (SMARCAL1 CD ) is composed of an SNF2-type doublestranded DNA motor ATPase fused to a HARP domain of unknown function. The mechanisms by which SMARCAL1 and other DNA translocases repair replication forks are poorly understood, in part because of a lack of structural information on the domains outside of the common ATPase motor. In the present work, we determined the crystal structure of the SMARCAL1 HARP domain and examined its conformation and assembly in solution by small angle X-ray scattering. We report that this domain is conserved with the DNA mismatch and damage recognition domains of MutS/MSH and NER helicase XPB, respectively, as well as with the putative DNA specificity motif of the T4 phage fork regression protein UvsW. Loss of UvsW fork regression activity by deletion of this domain was rescued by its replacement with HARP, establishing the importance of this domain in UvsW and demonstrating a functional complementarity between these structurally homologous domains. Mutation of predicted DNA-binding residues in HARP dramatically reduced fork binding and regression activities of SMARCAL1 CD . Thus, this work has uncovered a conserved substrate recognition domain in DNA repair enzymes that couples ATP-hydrolysis to remodeling of a variety of DNA structures, and provides insight into this domain's role in replication fork stability and genome integrity.replication restart | fork reversal A ccurate DNA replication is essential for genomic stability (1). Aberrant DNA structures, protein barriers, and chemically modified DNA thwart progression of the replication fork and lead to mutations, cytotoxicity, and increased chromosomal rearrangements (2-5). Uncoupling of polymerase and helicase activities at a stalled fork (6) results in an accumulation of singlestranded (ss) DNA (Fig. 1A), rendering the genome susceptible to nuclease cleavage and thereby increasing the probability of genetic rearrangements (7-9). Failure to stabilize stalled forks can lead to replisome dissociation and fork degradation or collapse. DNA damage response (DDR) pathways maintain genomic integrity by rectifying or protecting stalled or collapsed forks and regulating DNA repair (9-11). In humans, accumulation of the ssDNA-binding protein Replication Protein A (RPA) at stalled forks signals recruitment of the S-phase checkpoint kinase ATR (12-15), consequently triggering recruitment of proteins that promote sister chromatid cohesion and stabilize the histone/chromatin structure (16).Stabilization, repair, and restart of stalled forks can involve regression of the fork into a four-stranded "chicken foot" structure, in which the nascent DNA str...

show abstract

The DNA damage response: Balancing the scale between cancer and ageing

Cited by 55 publications

References 67 publications

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Chronic stress induces ageing-associated degeneration in rat Leydig cells

Structure-Function Relationship of DNA Repair Proteins: Lessons from BRCA1 and RAD51 Studies

A structure-specific nucleic acid-binding domain conserved among DNA repair proteins

Contact Info

Product

Resources

About