Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice

Schaetzlein, Sonja; Kodandaramireddy, N.R.; Ju, Zhenyu; Lechel, André; Stępczyńska, Anna; Lilli, Dana R.; Clark, Allan; Rudolph, Cornelia; Kühnel, Florian; Wei, Kai; Schlegelberger, Brigitte; Schirmacher, Peter; Kunkel, Thomas A.; Greenberg, Roger A.; Edelmann, Winfried; Rudolph, K. Lenhard

doi:10.1016/j.cell.2007.08.029

Cited by 139 publications

(111 citation statements)

References 71 publications

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“…For example, inactivation of Exo1 could facilitate escape from senescence and proliferation of mammalian cells with telomere defects. However, deletion of Exo1 did not appear to be a risk factor for cancer in mice lacking telomerase (Schaetzlein et al ., 2007). Conversely, Exo1 may instead facilitate genomic alterations relevant to carcinogenesis in DNA‐damaged human cells, similarly to its role in PAL cells.…”

Section: Discussionmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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SummaryTelomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres.

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Section: Discussionmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…Notably, it has recently been shown that a SNP in the EXO1 promoter leading to higher levels of EXO1 expression is enriched in female centenarians (Nebel et al 2009), suggesting a possible role for EXO1 activity in prevention of premature ageing, possibly by reducing cancer risk. By contrast, deletion of the nuclease activity of EXO1 in short-lived lategeneration telomerase-deficient mice rescues lifespan (Schaetzlein et al 2007). This rather unexpected finding may result from repression of the cyclinkinase inhibitor p21, which leads to the increased lifespan in terc −/− mice, as observed in mice lacking other components of MMR such as PMS2 (SieglCachedenier et al 2007) and which directly phenocopies p21 −/− Terc −/− mice (Choudhury et al 2007).…”

Section: Replication Fidelity Is Enhanced Through Nucleases Acting Inmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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“…Discovered in yeast (4), Exo1 participates in recombination (4,5), telomere maintenance (6, 7), mismatch repair (2,3,8), and processing of stalled replication forks (9). Consistent with its recombination function, mice devoid of Exo1 demonstrate a reduction in ssDNA formation at DSBs (7). Although RecJ and Exo1 have the same DNA degradation polarity, they differ in substrate specificity: RecJ acts preferentially on ssDNA (10), whereas Exo1 acts on dsDNA (4).…”

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confidence: 99%

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Nimonkar

Özsoy

Genschel³

et al. 2008

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

269

236

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The error-free repair of double-stranded DNA breaks by homologous recombination requires processing of broken ends. These processed ends are substrates for assembly of DNA strand exchange proteins that mediate DNA strand invasion. Here, we establish that human BLM helicase, a member of the RecQ family, stimulates the nucleolytic activity of human exonuclease 1 (hExo1), a 5 33 double-stranded DNA exonuclease. The stimulation is specific because other RecQ homologs fail to stimulate hExo1. Stimulation of DNA resection by hExo1 is independent of BLM helicase activity and is, instead, mediated by an interaction between the 2 proteins. Finally, we show that DNA ends resected by hExo1 and BLM are used by human Rad51, but not its yeast or bacterial counterparts, to promote homologous DNA pairing. This in vitro system recapitulates initial steps of homologous recombination and provides biochemical evidence for a role of BLM and Exo1 in the initiation of recombinational DNA repair.Bloom syndrome ͉ Rad51 ͉ recombination ͉ RecQ ͉ DNA pairing H omologous recombination contributes toward the maintenance of genomic integrity by accurately repairing doublestranded DNA (dsDNA) breaks. The recombinational repair of dsDNA breaks (DSBs) proceeds by successive reactions that start with processing of the broken DNA ends to reveal single-stranded DNA (ssDNA) (1). Processing requires the action of a helicase and/or nuclease. The resultant 3Ј-terminated ssDNA is used by a DNA strand exchange protein as the substrate for assembly of the nucleoprotein filament that is the active species in the search for homologous DNA and subsequent DNA pairing. It is unclear which enzymes in eukaryotes resect the DNA break to initiate recombination; however, much is known about the process in bacteria. In Escherichia coli, recombinational DNA repair occurs by either the RecBCD or the RecF pathway (1). RecBCD is a helicase/nuclease that processes dsDNA to produce 3Ј-tailed ssDNA onto which RecA is loaded. In the RecF pathway, a separate helicase and nuclease are used for resection of DSBs and ssDNA-gaps: RecQ, a 3Ј35Ј helicase, and RecJ, a 5Ј33Ј exonuclease (1).

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Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice

Cited by 139 publications

References 71 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

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