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

Han, Le; Mitchell, James R.; Hasty, Paul

doi:10.1016/j.mad.2008.02.002

Cited by 73 publications

(57 citation statements)

References 147 publications

(159 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…58 DSBs not only cause gross chromosomal translocations to promote tumorigenesis but also induce terminal cell cycle arrest and senescence at stalled replication forks. 56 This highlights their causal role in aging. In addition, DSBs arising as a result of telomeric erosion promote the constant activation of the DDR, accelerating the aging process.…”

Section: Accumulation Of Dna Damage In Agingmentioning

confidence: 96%

“…56,57 The aging process is driven by the accumulation of genetic alterations and disregulation of epigenetic signatures causing genomic instability, which may ultimately lead to cellular senescence, apoptosis and cancer. 58 DSBs not only cause gross chromosomal translocations to promote tumorigenesis but also induce terminal cell cycle arrest and senescence at stalled replication forks.…”

Section: Accumulation Of Dna Damage In Agingmentioning

confidence: 99%

See 1 more Smart Citation

γH2AX as a molecular marker of aging and disease

2010

View full text Add to dashboard Cite

Section: Accumulation Of Dna Damage In Agingmentioning

confidence: 96%

Section: Accumulation Of Dna Damage In Agingmentioning

confidence: 99%

γH2AX as a molecular marker of aging and disease

2010

View full text Add to dashboard Cite

“…DFSs are the primary cause of DNA double-strand breaks during replication (27)(28)(29), and are likely to be major contributors to the development of cancer and other pathologies, such as ones associated with aging (30,31). The inevitability of DFSs in longer genomes requires the presence of cellular mechanisms, which are able to deal with such errors in an efficient manner.…”

Section: Inevitability Is Mitigated By Containment In Longer Genomes Andmentioning

confidence: 99%

Inevitability and containment of replication errors for eukaryotic genome lengths spanning megabase to gigabase

Mamun

Albergante

Moreno

et al. 2016

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

View full text Add to dashboard Cite

The replication of DNA is initiated at particular sites on the genome called replication origins (ROs). Understanding the constraints that regulate the distribution of ROs across different organisms is fundamental for quantifying the degree of replication errors and their downstream consequences. Using a simple probabilistic model, we generate a set of predictions on the extreme sensitivity of error rates to the distribution of ROs, and how this distribution must therefore be tuned for genomes of vastly different sizes. As genome size changes from megabases to gigabases, we predict that regularity of RO spacing is lost, that large gaps between ROs dominate error rates but are heavily constrained by the mean stalling distance of replication forks, and that, for genomes spanning ∼100 megabases to ∼10 gigabases, errors become increasingly inevitable but their number remains very small (three or less). Our theory predicts that the number of errors becomes significantly higher for genome sizes greater than ∼10 gigabases. We test these predictions against datasets in yeast, Arabidopsis, Drosophila, and human, and also through direct experimentation on two different human cell lines. Agreement of theoretical predictions with experiment and datasets is found in all cases, resulting in a picture of great simplicity, whereby the density and positioning of ROs explain the replication error rates for the entire range of eukaryotes for which data are available. The theory highlights three domains of error rates: negligible (yeast), tolerable (metazoan), and high (some plants), with the human genome at the extreme end of the middle domain.T he proper maintenance of genetic information is of fundamental importance to the survival of all organisms, and many molecular mechanisms exist to ensure that the genetic sequence encoded by DNA is maintained unaltered generation after generation (1-3). To preserve the integrity of genetic information and to avoid aberrant ploidy, it is crucial that the entire DNA is copied exactly once; replicating only part of the DNA results in potential corruption of genes, and replicating certain parts of the DNA more than once would perturb chromosome structure and strongly affect gene dosage (4-6). Not surprisingly, regions of underreplicated and overreplicated DNA are common in cancer (7,8).DNA replication is a particularly complex process in eukaryotic organisms with large genomes distributed across multiple chromosomes. Multiple checkpoints exist to ensure that, once replication starts, the whole DNA is faithfully replicated before the chromosomes are segregated. Underreplication and overreplication of DNA are prevented by using predefined points of replication initiation called replication origins (ROs) (3, 9).During late mitosis and the G1 phase of the cell division cycle, each potential RO is "licensed" for a single initiation event by being loaded with minichromosome maintenance proteins 2-7 (MCM2-7) double hexamers. To prevent rereplication of DNA segments, the ability to license new origins...

show abstract

“…Diminished capacity for repair of double-strand breaks leads to cellular sensitivity to break-inducing agents [Jeggo, 1990], as expected, but also reduced proliferative capacity and premature cellular senescence [Nussenzweig et al, 1996]. At the organismal level, phenotypes vary from early developmental lethality to immunodeficiency [Rooney et al, 2004], failed neurogenesis and neurodegeneration [Lee and McKinnon, 2007], cancer predisposition [Difilippantonio et al, 2000], and progeria [Li et al, 2008]. Double-strand breaks are typically repaired by the homologous recombination (HR) or nonhomologous end joining (NHEJ) pathways (Fig.…”

Section: Dna Synthesis and Its Role In Double-strand Break Repairmentioning

confidence: 72%

DNA polymerases in nonhomologous end joining: Are there any benefits to standing out from the crowd?

Ramsden

Asagoshi

2012

Environ and Mol Mutagen

View full text Add to dashboard Cite

Chromosome breaks, often with damaged or missing DNA flanking the break site, are an important threat to genome stability. They are repaired in vertebrates primarily by nonhomologous end joining (NHEJ). NHEJ is unique among the major DNA repair pathways in that a continuous template cannot be used by DNA polymerases to instruct replacement of damaged or lost DNA. Nevertheless, at least 3 out of the 17 mammalian DNA polymerases are specifically employed by NHEJ. Biochemical and structural studies are further revealing how each of the polymerases employed by NHEJ possesses distinct and sophisticated means to overcome the barriers this pathway presents to polymerase activity. Still unclear, though, is how the resulting network of overlapping and nonoverlapping polymerase activities contributes to repair in cells. Environ. Mol. Mutagen. 53:741-751, 2012. V V C 2012 Wiley Periodicals, Inc.

show abstract

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

Cited by 73 publications

References 147 publications

γH2AX as a molecular marker of aging and disease

γH2AX as a molecular marker of aging and disease

Inevitability and containment of replication errors for eukaryotic genome lengths spanning megabase to gigabase

DNA polymerases in nonhomologous end joining: Are there any benefits to standing out from the crowd?

Contact Info

Product

Resources

About