Fos-dependent induction of Chk1 protects osteoblasts from replication stress

Schulze, Jochen; López-Contreras, Andrés J.; Uluçkan, Özge; Graña‐Castro, Osvaldo; Fernández-Capetillo, Óscar; Wagner, Erwin F.

doi:10.4161/cc.28923

Cited by 13 publications

(7 citation statements)

References 33 publications

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“…The majority of the observed tumors were lymphomas, which was confirmed by an enlarged spleen or lymph nodes containing CD3e positive cells ( Figure 3B). This is in agreement with our previous reports showing that increased CHK1 or RRM2 levels can reduce the DNA damage induced by oncogenes thereby facilitating oncogenic transformation or cell reprogramming [25,28,29].…”

Section: Extra Copies Of Chk1 and Rrm2 Mildly Increase The Prevalencesupporting

confidence: 93%

Supraphysiological protection from replication stress does not extend mammalian lifespan

Albers

Avram

Sbroggiò

et al. 2020

Aging

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Replication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the Chk1 and/or Rrm2 genes, which we previously showed extend the lifespan of a progeroid ATRhypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of Chk1, Rrm2 and Chk1/Rrm2 transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors-mainly lymphomas-irrespective of their genetic background. Interestingly, a higher but not statistically significant percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of normal aging.

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Section: Extra Copies Of Chk1 and Rrm2 Mildly Increase The Prevalencesupporting

confidence: 93%

Supraphysiological protection from replication stress does not extend mammalian lifespan

Albers

Avram

Sbroggiò

et al. 2020

Aging

Self Cite

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show abstract

“…3b). This is in agreement with our previous reports showing that increased CHK1 or RRM2 levels can reduce the DNA damage induced by oncogenes thereby facilitating oncogenic transformation or cell reprogramming [25,29,30].…”

Section: Extra Copies Of Chk1 and Rrm2 Mildly Increase The Prevalencesupporting

confidence: 93%

Supraphysiological protection from replication stress does not extend mammalian lifespan

Albers

Avram

Sbroggiò

et al. 2020

Preprint

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AbstractReplication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the Chk1 and/or Rrm2 genes, which we previously showed extend the lifespan of a progeroid ATR-hypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of Chk1, Rrm2 and Chk1/Rrm2 transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors -mainly lymphomas-irrespective of their genetic background. Interestingly, a slightly higher percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of “normal” aging.

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“…The presence of high levels of RS in cancer cells creates a pressure to acquire mutations that suppress RS and therefore facilitate their growth [ 16 - 18 ]. Supporting this view, CHK1 overexpression increases the efficiency of transformation by RAS, by suppressing oncogene-induced RS [ 19 , 20 ]. In addition, increased CHEK1 expression and/or gene copy number gains have been observed in tumors with a high degree of genomic instability, which correlated with an increased sensitivity to ATR or CHK1 inhibition [ 21 , 22 ].…”

Section: Resultsmentioning

confidence: 99%

Efficacy of ATR inhibitors as single agents in Ewing sarcoma

et al. 2016

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Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas.

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Fos-dependent induction of Chk1 protects osteoblasts from replication stress

Cited by 13 publications

References 33 publications

Supraphysiological protection from replication stress does not extend mammalian lifespan

Supraphysiological protection from replication stress does not extend mammalian lifespan

Supraphysiological protection from replication stress does not extend mammalian lifespan

Efficacy of ATR inhibitors as single agents in Ewing sarcoma

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