DNA Repair, Genome Stability, and Aging

In the paper

“Phosphorylation of p53 by ATM and kinases downstream of ATM is a major mechanism leading to upregulation of p53 levels and activity, although p53 also can be activated via ATM-independent mechanisms.”

In the paper

“Replicative life span of human cells is altered by culture under different oxygen tensions”

In the paper

“p53, through modulation of various downstream targets, triggers arrest/senescence or apoptosis (Meek, 2004”

What the sources say

• Not checked yetcites Meek, 2004 source

In the paper

“As normal byproducts of metabolism, ROS are a potential source of chronic, persistent DNA damage in all cells and may contribute to aging (Sohal and Weindruch, 1996”

What the sources say

• Not checked yetcites Sohal and Weindruch, 1996

In the paper

“The initial step in DSB repair is detection of the lesion, and this step involves the ataxia-telangiectasia mutated (ATM) kinase, other related phosphatidylinositol 3-kinase-like kinases (PIKKs), and other proteins (Figure 2; Bassing and Alt, 2004”

What the sources say

• Not checked yetcites Bassing and Alt, 2004

In the paper

“MEFs derived from M. musculus possess long telomeres and easily detectable telomerase activity (Itahana et al., 2004”

What the sources say

• Not checked yetcites Itahana et al., 2004 source

In the paper

“The G strand overhang is the substrate for the enzyme telomerase, which employs an RNA template, Terc, to extend telomeres during S phase, thereby countering the natural shortening of telomeres that would otherwise occur with each cell division.”

In the paper

“Activated ATM phosphorylates numerous proteins involved in the G1/S, intra-S, and G2/M checkpoint responses and additionally phosphorylates factors involved in DNA repair (Bassing and Alt, 2004”

What the sources say

• Not checked yetcites Bassing and Alt, 2004

In the paper

“In mammalian cells, the ends of the chromosomes consist of a terminal 3′ single-stranded tail, the G strand overhang, which is buried into adjacent double-stranded repetitive telomeric DNA, forming a protective “t loop” higher-order structure (de Lange, 2002”

What the sources say

• Not checked yetcites de Lange, 2002 source

In the paper

“which found that many nuclear genes involved in critical neural functions show reduced expression after age 40, concomitant with elevated levels of oxo8dG and DNA damage in their promoters.”

What the sources say

• Not checked yetcites Lu et al., 2004

In the paper

“Activated p53 stimulates or represses transcription of many target genes and coordinates checkpoint, senescence, and apoptosis pathways in response to DSBs and other signals.”

What the sources say

• Not checked yetcites Meek, 2004 source

In the paper

“However, senescent stromal cells can actually promote the growth of epithelial cancers, malignancies that occur with increased incidence in the elderly.”

What the sources say

• Not checked yetcites Krtolica and Campisi, 2002

In the paper

“Unrepaired or improperly repaired DSBs have serious potential consequences for the cell: cell death, senescence, dysregulation of cellular functions, genomic instability, and, in higher organisms, oncogenic transformation.”

What the sources say

• Not checked yetcites Bassing and Alt, 2004

In the paper

“senescent cells accumulate in vivo in mammals with increasing age and at sites of pathology (Itahana et al., 2004”

What the sources say

• Not checked yetcites Itahana et al., 2004 source

In the paper

“In brief, longer-lived species generally show higher cellular oxidative stress resistance and lower levels of mitochondrial ROS production than shorter-lived species.”

What the sources say

• Not checked yetcites Balaban et al., 2005 source

In the paper

“DNA damage accumulates with age”

• Also stated in: § Introduction · boosted

  “A large body of evidence argues that DNA damage and mutations accumulate with age in mammals (Vijg, 2000”

What the sources say

• Not checked yetcites Vijg, 2000 source

In the paper

“a strain of DNA-PKcs-deficient mice recently has been noted to exhibit age-related pathologies, with osteopenia, intestinal atrophy, thymic lymphoma, and reduced longevity (Espejel et al., 2004b”

What the sources say

• Not checked yetcites Espejel et al., 2004b

In the paper

“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

“Finally, ATM plays an important role in telomere maintenance; AT cells show shortened telomeres and an increased incidence of telomeric fusions (Pandita, 2002”

What the sources say

• Not checked yetcites Pandita, 2002 source

In the paper

“mice deficient for these four factors are very small and show widespread neuronal apoptosis during embryogenesis”

What the sources say

• Not checked yetcites Ferguson and Alt, 2001

In the paper

“NHEJ plays a critical role in general DNA DSB repair and, correspondingly, in the maintenance of genomic stability.”

In the paper

“In particular, such cells manifest sensitivity to DSB-inducing agents and have marked genomic instability; they also grow poorly and senesce prematurely in culture (Barzilai et al., 2002”

What the sources say

• Not checked yetcites Barzilai et al., 2002 source

In the paper

“Premature senescence and neuronal apoptosis, but not small size, are relieved by p53 deficiency.”

What the sources say

• Not checked yetcites Ferguson and Alt, 2001

In the paper

“These observations raise the possibility that other aspects of the ATM-deficient phenotype, including the premature aging observed in human patients, may be influenced by environment.”

In the paper

“Patients with mutations in the ATM gene suffer from Ataxia-Telangiectasia (AT), a condition characterized by a prematurely aged (progeroid) appearance, immunodeficiency, cerebellar degeneration, and cancer (Shiloh and Kastan, 2001”

What the sources say

• Not checked yetcites Shiloh and Kastan, 2001

In the paper

“a null mutation in a gene functioning downstream of p53 in the induction of apoptosis, p66Shc, confers oxidative stress resistance and extends mouse life span (Migliaccio et al., 1999”

What the sources say

• Not checked yetcites Migliaccio et al., 1999 source

In the paper

“In summary, NHEJ plays crucial roles in general and site-specific DSB repair, in telomere maintenance, and in maintenance of genomic stability.”

In the paper

“NHEJ is one of the two major DSB repair pathways in mammalian cells (Bassing and Alt, 2004”

What the sources say

• Not checked yetcites Bassing and Alt, 2004

In the paper

“Persistently elevated ROS levels in AT cells might cause chronic damage to DNA and other cellular macromolecules.”

In the paper

“Another potential function for ATM in suppressing progeroid phenotypes may be related to reported ATM functions in regulating intracellular ROS levels and sensitivity to these molecules (Barzilai et al., 2002; Ito et al., 2004”

What the sources say

• Not checked yetcites Barzilai et al., 2002 source
• Not checked yetcites Ito et al., 2004 source

In the paper

“at the same time it promotes cellular senescence and apoptosis in response to DNA damage, potentially contributing to the clinical changes of aging.”

In the paper

“ATM deficiency in mice recapitulates many of these phenotypes, although the progeroid features of the mouse models are less prominent than in the human disease.”

In the paper

“Moreover, mice lacking both ATM and Terc have higher levels of telomeric dysfunction than generation-matched Terc-deficient mutants, as well as proliferative defects in multiple tissues, decreased survival, and clinical evidence of premature aging (Wong et al., 2003”

What the sources say

• Not checked yetcites Wong et al., 2003 source

In the paper

“However, two mouse strains that express C-terminal p53 fragments along with full-length p53 have been reported to show accelerated aging phenotypes and a lower incidence of malignancy (Maier et al., 2004; Tyner et al., 2002”

What the sources say

• Not checked yetcites Maier et al., 2004 source
• Not checked yetcites Tyner et al., 2002 source

In the paper

“BRCA1Δ11/Δ11 MEFs show increased chromosomal abnormalities and premature cellular senescence, and BRCA1Δ11/Δ11 embryos show tissue SA-β-galactosidase activity, a marker of senescence.”

What the sources say

• Not checked yetcites Cao et al., 2003b

In the paper

“although only cerebellar defects have been described in detail in these animals (Murai et al., 2001”

What the sources say

• Not checked yetcites Murai et al., 2001 source

In the paper

“Additionally, these XPDTTD mice show aging-associated changes such as wasting, scoliosis, osteoporosis, and melanocyte loss (de Boer et al., 2002”

What the sources say

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

In the paper

“NER can be subdivided into two pathways, global genome NER (GG-NER) and transcription-coupled NER (TC-NER), which differ with respect to the lesion detected and some of the factors involved (Mitchell et al., 2003; Figure 5”

What the sources say

• Not checked yetcites Mitchell et al., 2003 source

In the paper

“mice homozygous for a BRCA1 hypomorphic allele and haploinsufficient for p53 (BRCA1Δ11/Δ11/p53+/−) are viable and have many features reminiscent of accelerated aging: wasting, skin atrophy, osteopenia, and malignancy (Cao et al., 2003b”

What the sources say

• Not checked yetcites Cao et al., 2003b

In the paper

“cells deficient in Ligase IV and ATM or Terc and ATM show high levels of genomic instability and very rapid senescence (Sekiguchi et al., 2001; Wong et al., 2003”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Sekiguchi et al., 2001; Wong et al., 2003

In the paper

“homozygosity for a Rad50 hypomorphic allele (Rad50s/s) permits viability; Rad50s/s mice show a shortened life span, cancer predisposition, and hematopoietic stem cell and spermatogenic failure (Bender et al., 2002”

What the sources say

• Not checked yetcites Bender et al., 2002 source

In the paper

“Current findings suggest, however, that aging phenotypes likely do not result from a failure of DSB repair alone but instead from a loss of other functions or combinations of functions of these proteins, perhaps in concert with environmental factors, such as housing conditions and/or infection and/or background mutations.”

In the paper

“Alternatively, the involvement of XPD and the CSB proteins in transcription suggests that impaired transcription of critical genes may play a role in causing these progeroid phenotypes, perhaps interacting with the repair defects in a complicated fashion.”

In the paper

“WS patients develop premature graying, cataract, loss of subcutaneous fat, skin atrophy, osteoporosis, diabetes, atherosclerosis, and malignancies.”

What the sources say

• Not checked yetcites Goto, 1997 source

In the paper

“Defects in Rad50 or BRCA1 cause progeroid phenotypes.”

In the paper

“mutations in genes involved in this pathway do not produce aging manifestations: they are either lethal or confer no obvious phenotypes (Hasty et al., 2003”

What the sources say

• Not checked yetcites Hasty et al., 2003 source

In the paper

“Such complexities also may likely apply to other DNA repair proteins implicated in the suppression of aging as well”

In the paper

“Defects in the TC-NER-specific factors CSA or CSB lead to Cockayne syndrome in humans, a severely debilitating disorder with striking progeroid features.”

What the sources say

• Not checked yetcites Mitchell et al., 2003 source

In the paper

“Deficiency of Mre11, Nbs1, or Rad50 is not compatible with cellular survival (Stracker et al., 2004”

What the sources say

• Not checked yetcites Stracker et al., 2004 source

In the paper

“degenerative changes in these models occur in both highly proliferative (intestine and skin) and relatively less proliferative (bone and liver) tissues, apparently sparing many other tissues of both types.”

In the paper

“leading to tissue attrition and aging.”

In the paper

“Additionally, SIRT1, like Sir2, has recently been shown to directly modify chromatin and silence transcription (Vaquero et al., 2004”

What the sources say

• Not checked yetcites Vaquero et al., 2004 source

In the paper

“it was proposed that WRN-deficient mice may not demonstrate a strong phenotype due to the abundant mouse telomere reserve (Lombard et al., 2000”

What the sources say

• Not checked yetcites Lombard et al., 2000 source

In the paper

“In addition, as discussed above, environmental factors including housing conditions, infectious agents, diet, and many other influences, also likely play a significant role in the expression of aging phenotypes in mouse models and, perhaps, in humans as well.”

In the paper

“to suppress recombination and turns off transcription at multiple genomic loci (Blander and Guarente, 2004”

What the sources say

• Not checked yetcites Blander and Guarente, 2004

In the paper

“The role of SIRT1 in mammalian longevity has not yet been directly tested, since on a pure strain background SIRT1-deficient animals die very early as a consequence of multiple developmental defects (Cheng et al., 2003; McBurney et al., 2003”

What the sources say

• Not checked yetcites Cheng et al., 2003 source
• Not checked yetcites McBurney et al., 2003 source

In the paper

“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”

What the sources say

• Not checked yetcites Kaeberlein et al., 1999 source

In the paper

“Overall, the phenotype of the WRN/Terc double knockout mouse argues that defective telomere maintenance is an important factor in producing the premature aging-like aspects of WS in humans, although it does not exclude a role for other functions of WRN at nontelomeric sites.”

In the paper

“Also, it must be remembered that many of the DNA repair genes and factors implicated in suppressing aging also play roles in cellular processes other than DNA repair, and therefore aging-like phenotypes might be enhanced by impairment of other cellular functions in conjunction with altered DNA repair.”

In the paper

“This metabolic switch alters the metabolism of the cell, increasing the NAD/NADH ratio and/or decreasing levels of the Sir2 inhibitor nicotinamide, in turn activating Sir2 and increasing rDNA stability (reviewed in Blander and Guarente, [2004]”

What the sources say

• Not checked yetcites Blander and Guarente, 2004

In the paper

“SIRT1 possesses a large and growing list of targets, some of which, including p53 and forkhead transcription factors (mammalian homologs of Daf-16), modulate cellular resistance to oxidative and genotoxic stress (Blander and Guarente, 2004”

What the sources say

• Not checked yetcites Blander and Guarente, 2004

In the paper

“Sir2 family members may play a general role in mediating caloric restriction (Sohal and Weindruch, 1996”

What the sources say

• Not checked yetcites Sohal and Weindruch, 1996

In the paper

“WRN also interacts with the telomeric protein TRF2 and can unwind and degrade telomeric D loop structures.”

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

“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”

What the sources say

• Not checked yetcites Kaeberlein et al., 1999 source

In the paper

“It has been proposed that Sir2 activity ties the energy status of the yeast cell to longevity (Blander and Guarente, 2004; Lin et al., 2000”

What the sources say

• Not checked yetcites Blander and Guarente, 2004
• Not checked yetcites Lin et al., 2000 source

In the paper

“Phenotypes ordinarily seen in late-generation Terc-deficient animals also occur earlier in the compound mutants and are associated with a greater degree of telomeric dysfunction.”

In the paper

“In mammals, there are seven Sir2 family members, designated SIRT1–SIRT7 (Frye, 2000”

What the sources say

• Not checked yetcites Frye, 2000 source

In the paper

“although in yeast the involvement of Sir2 in CR appears to be strain specific (Kaeberlein et al., 2004”

What the sources say

• Not checked yetcites Kaeberlein et al., 2004 source

In the paper

“Aging encompasses a wide spectrum of degenerative processes, many of which are quite nonspecific, both clinically and pathologically (Harrison, 1994”

What the sources say

• Not checked yetcites Harrison, 1994 source

In the paper

“Mammalian aging is not likely a single process but rather the decline of many somatic functions, heavily influenced by the environment; this is a complex interplay that is extremely difficult to model accurately.”

In the paper

“A related difficulty is that premature aging models fail to recapitulate all aspects of aging but are instead “segmental progerias” (Hasty and Vijg, 2004; Miller, 2004”

What the sources say

• Not checked yetcites Hasty and Vijg, 2004
• Not checked yetcites Miller, 2004 source

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.”

In the paper

“In models of premature aging, the most vulnerable system fails first, leading to death and precluding gain of insights from effects on other, potentially more relevant, organ systems.”

In the paper

“All mouse models that link DNA repair to aging possess defects in DNA repair and have shortened life spans.”