DNA Repair, Genome Stability, and Aging

In the paper

“Such uncapped telomeres are then recognized by the cell cycle checkpoint machinery as DNA damage, leading to cell cycle arrest (Ben-Porath and Weinberg, 2004”

What the sources say

• Not checked yetcites Ben-Porath and Weinberg, 2004 source

In the paper

“Caloric restriction, an intervention that extends life span in many organisms, likely decreases ROS production (Barja, 2004”

What the sources say

• Not checked yetcites Barja, 2004 source

In the paper

“In many primary human cell lines, replicative senescence occurs secondary to attrition of the ends of the chromosomes, the telomeres, in a process termed “intrinsic senescence” (Itahana et al., 2004”

What the sources say

• Not checked yetcites Itahana et al., 2004 source

In the paper

“many mutations in DNA repair genes that cause premature aging phenotypes also confer premature replicative senescence (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“Such analyses have revealed considerable variation in mutation spectra between different tissues.”

In the paper

“In model organisms, many mutations that promote longevity concomitantly increase oxidative stress resistance (Finkel and Holbrook, 2000”

What the sources say

• Not checked yetcites Finkel and Holbrook, 2000

In the paper

“Terc deficiency in mice leads to progressive telomere attrition in successive mouse generations”

What the sources say

• Not checked yetcites Espejel and Blasco, 2002

In the paper

“This highlights the difficulty of accurately measuring ROS and oxidative damage experimentally.”

In the paper

“Of note, late-generation Terc-deficient mice show some signs of accelerated aging (Lee et al., 1998; Rudolph et al., 1999”

What the sources say

• Not checked yetcites Lee et al., 1998 source
• Not checked yetcites Rudolph et al., 1999 source

In the paper

“Critically short telomeres trigger the onset of senescence through a process that may involve loss of the t loop structure and/or loss of protective proteins (referred to as “uncapping”).”

What the sources say

• Not checked yetcites Ben-Porath and Weinberg, 2004 source

In the paper

“As outlined below, the efficiency of cellular DNA repair machinery itself may decline with age.”

In the paper

“In addition, levels of 8-oxoguanine (oxo8dG), a major product of oxidative damage to DNA, accumulate with age (Hamilton et al., 2001”

What the sources say

• Not checked yetcites Hamilton et al., 2001 source

In the paper

“Cytogenetically visible lesions such as translocations, insertions, dicentrics, and acentric fragments also accumulate in aging mammalian cells.”

What the sources say

• Not checked yetcites Vijg, 2000 source

In the paper

“There is some evidence that the intrinsic fidelity and activity of such systems in different species may influence the rate of age-associated functional decline (Hart and Setlow, 1974”

What the sources say

• Not checked yetcites Hart and Setlow, 1974 source

In the paper

“despite accumulating higher levels of nuclear and mitochondrial 8oxodG with age (Van Remmen et al., 2003”

What the sources say

• Not checked yetcites Van Remmen et al., 2003 source

In the paper

“However, the high levels of oxidative DNA damage found by these investigators is at odds with other much lower estimates of the amount of oxidatively damaged DNA in cells (Hamilton et al., 2001”

What the sources say

• Not checked yetcites Hamilton et al., 2001 source

In the paper

“Perturbations in ATM function can lead to symptoms of accelerated aging.”

What the sources say

• Not checked yetcites Shiloh and Kastan, 2001

In the paper

“ROS and many other DNA-damaging agents can cause cells to enter a state of irreversible cell cycle arrest accompanied by characteristic morphologic and functional alterations, termed senescence (Ben-Porath and Weinberg, 2004”

What the sources say

• Not checked yetcites Ben-Porath and Weinberg, 2004 source

In the paper

“Among long-lived mutants, the correlation with oxidative stress resistance is a frequent but not universal one”

In the paper

“An important target of ATM is the p53 protein, which plays a role in the cellular response to numerous genotoxic insults including DSBs.”

In the paper

“and telomere shortening in these cells is itself accelerated by elevated levels of oxidative stress.”

In the paper

“in some mutants, longevity occurs despite unchanged resistance to ROS or other forms of stress.”

In the paper

“In many types of human cells, including fibroblasts, telomeres shorten with each successive generation.”

In the paper

“In mice and humans, mutations in certain DNA repair genes lead to phenotypes that, in some respects, caricature aging.”

What the sources say

• Not checked yetcites Table 1
• Not checked yetcites Table 2

In the paper

“and rapid senescence in embryonic fibroblasts derived from late-generation animals (Espejel and Blasco, 2002”

What the sources say

• Not checked yetcites Espejel and Blasco, 2002

In the paper

“the Polycomb group repressor Bmi1 appears to control levels of hematopoietic stem cells via negatively regulating the induction of senescence specifically in these stem cells.”

In the paper

“and many mouse and human models of premature aging are accompanied by premature cellular senescence in vitro (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“Instead, senescence of wild-type MEFs occurs primarily in response to oxidative DNA damage incurred during cell culture (Parrinello et al., 2003”

What the sources say

• Not checked yetcites Parrinello et al., 2003 source

In the paper

“It is now clear that senescence can be induced by a variety of different types of cellular injury (Figure 1).”

In the paper

“Thus, MEFs ordinarily do not senesce due to telomeric attrition.”

In the paper

“These differences likely reflect functional characteristics of those tissues, such as mitotic rate, transcriptional activity, metabolism, and the action of specific DNA repair systems.”

In the paper

“Additionally, mice heterozygous for a mutation in the mitochondrial enzyme that processes superoxide, Sod2, live out a normal lifespan”

What the sources say

• Not checked yetcites Van Remmen et al., 2003 source

In the paper

“Various lines of evidence suggest that p53 plays opposing roles in the aging process.”

In the paper

“Thus, the former phenotypes occur as a response to, rather than as a direct consequence of, unrepaired DSBs (Ferguson and Alt, 2001”

What the sources say

• Not checked yetcites Ferguson and Alt, 2001 source

In the paper

“The phenotypes of ATM deficiency are influenced by environmental conditions.”

What the sources say

• Not checked yetcites Schubert et al., 2004 source
• Not checked yetcites Browne et al., 2004 source
• Not checked yetcites Petiniot et al., 2002 source

In the paper

“NHEJ also promotes telomeric fusions in some circumstances.”

What the sources say

• Not checked yetcites Espejel et al., 2002a, 2002b; Smogorzewska et al., 2002

In the paper

“Thus, p53 function may display antagonistic pleiotropy (Campisi, 2002”

What the sources say

• Not checked yetcites Campisi, 2002 source

In the paper

“targeted ablation of Ku70 results in dramatically reduced Ku80 levels (Gu et al., 1997”

What the sources say

• Not checked yetcites Gu et al., 1997

In the paper

“it promotes cell death in response to oxidative stress”

What the sources say

• Not checked yetcites Migliaccio et al., 1999 source

In the paper

“In this context, the premature cellular senescence phenotype of ATM deficiency is rescued by p53 deficiency (Xu et al., 1998”

What the sources say

• Not checked yetcites Xu et al., 1998

In the paper

“it increases constitutive intracellular ROS levels”

What the sources say

• Not checked yetcites Migliaccio et al., 1999 source

In the paper

“a line of Ku80-deficient mice prematurely exhibits age-specific changes including osteopenia, atrophic skin, liver lesions, and shortened life span (Vogel et al., 1999”

What the sources say

• Not checked yetcites Vogel et al., 1999 source

In the paper

“Increased telomere end-to-end fusions are observed in the setting of the telomeric attrition associated with Terc deficiency or inhibition of TRF2, a protein thought to function in end capping, and these end-to-end fusions are eliminated in NHEJ-deficient backgrounds (Espejel et al., 2002a, 2002b; Smogorzewska et al., 2002”

What the sources say

• Not checked yetcites Espejel et al., 2002a, 2002b; Smogorzewska et al., 2002

In the paper

“p53-dependent responses are critical in mediating the premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants (Ferguson and Alt, 2001”

What the sources say

• Not checked yetcites Ferguson and Alt, 2001 source

In the paper

“Genomic instability or DNA repair defects of ATM deficiency could contribute to the aging-like features of this disorder (see below).”

In the paper

“the lack of a consistent aging-like phenotype in other lines of long-lived Ku-, DNA-PKcs-, or Artemis-deficient mice is difficult to explain if NHEJ plays a general role in delaying manifestations of aging (Karanjawala and Lieber, 2004”

What the sources say

• Not checked yetcites Karanjawala and Lieber, 2004

In the paper

“Only nonphysiologic activation of p53 leads to progeria, as mice expressing extra copies of wild-type p53 under the control of its own promoter do not show signs of premature aging (Garcia-Cao et al., 2002”

What the sources say

• Not checked yetcites Garcia-Cao et al., 2002 source

In the paper

“Mice with targeted inactivating mutations in NHEJ genes display phenotypes that reflect loss of these functions (Ferguson and Alt, 2001”

What the sources say

• Not checked yetcites Ferguson and Alt, 2001 source

In the paper

“Thus, human AT patients may show aging-like effects, at least in part, as a consequence of telomeric dysfunction, an effect that ordinarily may be masked in the mouse due to the long telomeres of this organism.”

In the paper

“The observation that phenotypes resembling accelerated aging have been described in one strain each of Ku80- and DNA-PKcs-deficient mice potentially supports this model.”

What the sources say

• Not checked yetcites Vogel et al., 1999 source
• Not checked yetcites Espejel et al., 2004b

In the paper

“However, given the lack of an AT-like phenotype of the Sod2+/− mouse, progeroid features of ATM deficiency likely reflect more than increased ROS levels.”

In the paper

“Additionally, the frequency of thymic lymphoma varies among different strains of ATM-deficient mice, a finding that might reflect different background mutations and/or housing conditions and the types of pathogens present (Petiniot et al., 2002”

What the sources say

• Not checked yetcites Petiniot et al., 2002 source

In the paper

“genetic studies support the notion that NHEJ plays an important role in the repair of ROS-induced DNA lesions (Karanjawala and Lieber, 2004”

What the sources say

• Not checked yetcites Karanjawala and Lieber, 2004

In the paper

“MEFs deficient for XRCC4, Ligase IV, Ku70, or Ku80 (but not DNA-PKcs or Artemis) senesce prematurely in culture”

What the sources say

• Not checked yetcites Ferguson and Alt, 2001 source

In the paper

“Ku80-deficient mice are found to have a low rate of mutations at a marker locus (Rockwood et al., 2003”

What the sources say

• Not checked yetcites Rockwood et al., 2003 source

In the paper

“Thus, by ligating uncapped telomeres, NHEJ may actually promote genomic instability.”

In the paper

“Neurological dysfunction in this model can similarly be ameliorated via antioxidant treatment (Browne et al., 2004”

What the sources say

• Not checked yetcites Browne et al., 2004 source

In the paper

“at least three core NHEJ factors, namely Ku70, Ku80, and DNA-PKcs, localize to telomeres (d'Adda di Fagagna et al., 2001”

What the sources say

• Not checked yetcites d'Adda di Fagagna et al., 2001 source

In the paper

“In the ATM-deficient mouse, the onset of T cell lymphoma can be delayed by treatment with an antioxidant, suggesting that dietary factors impact on the expression of this condition (Schubert et al., 2004”

What the sources say

• Not checked yetcites Schubert et al., 2004 source

In the paper

“Stalled RNA polymerase provides a signal for activation of p53-dependent apoptosis (Ljungman and Lane, 2004”

What the sources say

• Not checked yetcites Ljungman and Lane, 2004

In the paper

“These patients show defects in transcription of hair- and skin-specific transcripts (and perhaps other mRNAs) (Bergmann and Egly, 2001”

What the sources say

• Not checked yetcites Bergmann and Egly, 2001

In the paper

“Late generation Terc-deficient mice have an uncharacterized DSB repair defect (Wong et al., 2000”

What the sources say

• Not checked yetcites Wong et al., 2000 source

In the paper

“Baseline p53 protein levels are higher in BRCA1Δ11/Δ11/p53+/− mice than in p53+/− control animals.”

What the sources say

• Not checked yetcites Cao et al., 2003b

In the paper

“Ku80/Terc and DNA-PKcs/Terc double deficient mice show exacerbation of intestinal atrophy and other aging-like phenotypes of Terc deficiency (Espejel et al., 2004a”

What the sources say

• Not checked yetcites Espejel et al., 2004a

In the paper

“suggesting that in the setting of impaired transcription and/or TC-NER, a total lack of NER is extremely deleterious.”

In the paper

“Numerous human patients and mouse strains with defects in different NER factors exist, and some have phenotypes reminiscent of premature aging (Mitchell et al., 2003”

What the sources say

• Not checked yetcites Mitchell et al., 2003 source

In the paper

“The human disease WS represents the best model for premature aging in humans (Goto, 1997”

What the sources say

• Not checked yetcites Goto, 1997 source

In the paper

“These observations argue against a simple relationship between mitotic status and dependence on NHEJ in the suppression of aging.”

In the paper

“CSA- and CSB-deficient mice show much milder phenotypes than their human counterparts (Mitchell et al., 2003”

What the sources say

• Not checked yetcites Mitchell et al., 2003 source

In the paper

“WS cells senesce prematurely in culture.”

What the sources say

• Not checked yetcites Goto, 1997 source

In the paper

“Thus, in both the Rad50s/s and BRCA1Δ11/Δ11/p53+/− mice, signs of premature aging occur as a consequence of the p53-mediated responses to unrepaired DNA damage.”

In the paper

“WRN plays a role in the maintenance of overall genomic stability, and WRN may be involved in multiple DNA repair pathways (Bachrati and Hickson, 2003”

What the sources say

• Not checked yetcites Bachrati and Hickson, 2003

In the paper

“Two factors with roles in HR, Rad50 and BRCA1 (breast cancer susceptibility gene-1), appear linked to aging-like phenotypes in mouse models.”

In the paper

“Homozyogous inactivation of BRCA1 results in early embryonic lethality (Valerie and Povirk, 2003”

What the sources say

• Not checked yetcites Valerie and Povirk, 2003

In the paper

“Mice bearing a targeted mutation in XPD that recapitulates a human TTD mutation show similar manifestations to human TTD patients.”

What the sources say

• Not checked yetcites de Boer et al., 2002 source

In the paper

“suggesting that multiple functions of XPD are defective in these individuals.”

In the paper

“WRN-deficient mice do not recapitulate human WS (Bachrati and Hickson, 2003”

What the sources say

• Not checked yetcites Bachrati and Hickson, 2003

In the paper

“introduction of telomerase into WS fibroblasts can rescue their premature senescence (Wyllie et al., 2000”

What the sources say

• Not checked yetcites Wyllie et al., 2000 source

In the paper

“Recent experiments using mice bearing targeted mutations in WRN provide evidence that, with respect to aging, the most relevant sites of WRN function are the telomeres.”

In the paper

“The aging-like phenotypes in human CS patients and in XPDTTD, XPDTTD/XPA, and CSB/XPA mouse mutants may be explained by the fact that a failure to repair lesions in transcribed genes can result in cell death, leading to tissue attrition and aging.”

In the paper

“lesions in some factors involved in NER can lead to premature aging syndromes in mice and humans.”

In the paper

“a failure to repair lesions in transcribed genes can result in cell death”

In the paper

“The attrition of the hematopoietic and male germ cell lineages occurs in large measure due to p53-mediated signaling triggered by genomic instability (Bender et al., 2002”

What the sources say

• Not checked yetcites Bender et al., 2002 source

In the paper

“targeted inactivation of either Ku80 or DNA-PKcs, but not in Ligase IV or XRCC4, demonstrates synthetic lethality with ATM deficiency.”

What the sources say

• Not checked yetcites Sekiguchi et al., 2001 source

In the paper

“The degenerative changes in afflicted strains of DNA-PKcs- and Ku80-deficient mice affect only a limited subset of organs.”

In the paper

“WRN plays a role in the maintenance of overall genomic stability, and WRN may be involved in multiple DNA repair pathways (Bachrati and Hickson, 2003”

What the sources say

• Not checked yetcites Bachrati and Hickson, 2003

In the paper

“There is compelling evidence that this phenotype results from p53-dependent responses to unrepaired DNA damage (Cao et al., 2003b”

What the sources say

• Not checked yetcites Cao et al., 2003b

In the paper

“Similarly, mice deficient in both CSB and XPA also die within a few weeks after birth”

What the sources say

• Not checked yetcites Murai et al., 2001 source

In the paper

“Defects in proteins with less well-defined functions in DNA repair can lead to aging phenotypes as well.”

In the paper

“human WS cells show telomeric instability (Schulz et al., 1996; Tahara et al., 1997”

What the sources say

• Not checked yetcites Schulz et al., 1996 source
• Not checked yetcites Tahara et al., 1997 source

In the paper

“Genomic instability is detectable in cells derived from this animal.”

What the sources say

• Not checked yetcites Bender et al., 2002 source

In the paper

“Sir2-driven increased longevity in C. elegans requires the Daf-16 transcription factor (Tissenbaum and Guarente, 2001”

What the sources say

• Not checked yetcites Tissenbaum and Guarente, 2001

In the paper

“the premature senescence of human WS fibroblasts is p53 dependent (Davis et al., 2003”

What the sources say

• Not checked yetcites Davis et al., 2003 source

In the paper

“The excision and replication of rDNA circles is an important cause of mortality in yeast when life span is measured in this fashion (Sinclair and Guarente, 1997”

What the sources say

• Not checked yetcites Sinclair and Guarente, 1997 source

In the paper

“the impact of such lesions may be enhanced by age-related compromise of DNA repair.”

In the paper

“The latter observation suggests that cellular checkpoint functions may be involved in producing the clinical features of WS.”

In the paper

“In the models discussed above, decreased genomic stability is associated with shortened life span.”

In the paper

“In addition, p53-mediated senescence and apoptosis, in response to DNA damage, also likely contribute to aging (Figure 6).”

In the paper

“While ROS are likely to be one important source of this damage, there are numerous other cellular and environmental sources of damage”

In the paper

“When nutrients are scarce, yeast cells preferentially employ respiration rather than fermentation to generate ATP (Lin et al., 2002”

What the sources say

• Not checked yetcites Lin et al., 2002 source

In the paper

“WRN can be detected at the telomeres in the absence of telomerase function in mammalian cells (Johnson et al., 2001; Opresko et al., 2004”

What the sources say

• Not checked yetcites Johnson et al., 2001 source
• Not checked yetcites Opresko et al., 2004 source

In the paper

“The hypothesis that nuclear DNA, a critically important cellular constituent that cannot be replaced, is an important target of age-related change is supported by evidence that nuclear DNA damage and mutations accumulate with age.”

In the paper

“In the WRN/Terc double deficient animals, phenotypes reminiscent of human WS that are not observed in either single mutant are present: osteopenia, diabetes, and sarcomas.”

What the sources say

• Not checked yetcites Chang et al., 2004 source
• Not checked yetcites Du et al., 2004

In the paper

“an intervention capable of extending life span in many different organisms from yeast to mammals (Cohen et al., 2004; Howitz et al., 2003; Lin et al., 2000; Rogina and Helfand, 2004; Wood et al., 2004”

What the sources say

• Not checked yetcites Cohen et al., 2004 source
• Not checked yetcites Howitz et al., 2003 source
• Not checked yetcites Lin et al., 2000 source

In the paper

“Accumulation of mutations in critical genes may be one general mechanism by which compromised DNA repair could contribute to aging.”

In the paper

“Sgs1p, the S. cerevisiae WRN homolog, is required for recombinational telomere maintenance in telomerase-deficient cells in yeast (Cohen and Sinclair, 2001; Huang et al., 2001; Johnson et al., 2001”

What the sources say

• Not checked yetcites Cohen and Sinclair, 2001
• Not checked yetcites Huang et al., 2001 source
• Not checked yetcites Johnson et al., 2001 source

In the paper

“In S. cerevisiae, the chromatin regulatory factor Sir2 (silent information regulator-2) functions as an NAD-dependent histone deacetylase (Imai et al., 2000”

What the sources say

• Not checked yetcites Imai et al., 2000 source

In the paper

“However, genetic background effects almost certainly play an important role in modifying the aging-like manifestations of DNA repair deficiencies.”

In the paper

“The Sir2 family of proteins provides an example in which increased genomic stability extends life span (Blander and Guarente, 2004”

What the sources say

• Not checked yetcites Blander and Guarente, 2004

In the paper

“most premature aging syndromes are caused by mutations in genes encoding proteins involved in DNA repair (Karanjawala and Lieber, 2004”

What the sources say

• Not checked yetcites Karanjawala and Lieber, 2004

In the paper

“SIRT2 and SIRT3 are unlikely to play this role, because these proteins are cytoplasmic and mitochondrial, respectively, rather than chromatin associated (Blander and Guarente, 2004”

What the sources say

• Not checked yetcites Blander and Guarente, 2004

In the paper

“Indeed, the fact that lesions in several disparate repair systems cause phenotypes that are broadly similar to one another (Table 1) is consistent with the notion that the specific chemical nature of the accumulated DNA lesions may be less important than their ability to activate the common cellular checkpoint machinery.”

In the paper

“These observations suggest that WRN may play a role in providing telomeric access to other factors involved in telomere maintenance (Machwe et al., 2004; Opresko et al., 2004; Orren et al., 2002”

What the sources say

• Not checked yetcites Machwe et al., 2004 source
• Not checked yetcites Opresko et al., 2004 source
• Not checked yetcites Orren et al., 2002 source

In the paper

“Strikingly, overexpression or pharmacologic activation of Sir2 in worms and flies also extends life span (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001; Wood et al., 2004”

What the sources say

• Not checked yetcites Rogina and Helfand, 2004 source
• Not checked yetcites Tissenbaum and Guarente, 2001
• Not checked yetcites Wood et al., 2004 source

In the paper

“This hypothesis has been proven correct by the generation of mice deficient in both WRN and Terc (Chang et al., 2004; Du et al., 2004”

What the sources say

• Not checked yetcites Chang et al., 2004 source
• Not checked yetcites Du et al., 2004

In the paper

“Thus, aging is likely the outcome of a complex interplay between the genetic endowment of an organism and the stresses placed upon it by its particular environment.”

In the paper

“Factors implicated in organismal decline in genetic models might not play a role in the normal aging processes.”

In the paper

“In this regard, the myriad histopathologic changes of normal aging (Table 2) correspond poorly with the changes that occur in models of premature aging (Table 1).”

In the paper

“For these reasons, genetic models of extended life span are likely to be more informative than models with reduced longevity with respect to physiologically relevant causes of decline and mortality; in such long-lived organisms, life span-limiting factors must of necessity be counteracted.”