A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging

Murga, Matilde; Bunting, Samuel F.; Montaña, Maria F; Soria, Rebeca; Mulero, Francisca; Cañamero, Marta; Lee, Youngsoo; McKinnon, Peter J.; Nussenzweig, André; Fernández-Capetillo, Óscar

doi:10.1038/ng.420

Cited by 326 publications

(418 citation statements)

References 47 publications

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“…In agreement with the previous mouse data, ATR inhibitors were particularly toxic for cells expressing Sphase promoting oncogenes such as cyclin E, specially in the context of p53-deficiency [81]. Additionally, ATR inhibition was toxic for ATM deficient cells [87], a synthetic lethal effect that had already been described with mouse models [9]. The availability of these compounds has allowed the discovery of new synthetic lethal interactions that confer sensitivity to ATR inhibitors and which so far include mutations in XRCC1, ERCC1-XPF or BRCA1 [89][90][91].…”

Section: Targeting Rs In Cancer Treatmentsupporting

confidence: 90%

“…Whereas ATR deficiency is not viable, a synonymous mutation that compromises ATR mRNA splicing leads to a severe reduction of ATR levels and a human hereditary syndrome known as Seckel, associated to dwarfism and microcephaly [8]. A humanized mouse model of ATR-Seckel recapitulates the symptoms of the human patients, and revealed that ATR hypomorphism limits mammalian lifespan due to a generalized accumulation of RS during embryogenesis [9]. In contrast to other genomic instability syndromes that show cancer predisposition, ATR-Seckel mice do not develop spontaneous tumours.…”

Section: Introductionmentioning

confidence: 99%

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Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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Section: Targeting Rs In Cancer Treatmentsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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“…HSC mobilization is linked to stem cell functional depletion. 5,32 We asked whether 6 months of HU treatment alters the competitive repopulating ability of Bid þ / þ and Bid À / À bone marrow. Lineage-depleted Bid þ / þ (CD45.2) and Bid À / À (CD45.2) bone marrow cells were transplanted into lethally irradiated congenic recipient mice (CD45.1) with equal amounts of lineage-depleted competitor bone marrow cells (CD45.1).…”

Section: Resultsmentioning

confidence: 99%

Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress

2012

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Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin À Sca1 þ Kit þ (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid À / À MPCs demonstrate increased sensitivity to HU and are depleted. Bid À / À LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid À / À MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid À / À mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.

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“…Several brain diseases such as Alzheimer's disease or Seckel syndrome may be linked to replicative stress. 34,35 In the brain, Cip/Kip proteins have been involved in the regulation of neurogenesis and maintenance of neural stem cells homeostasis. p27 Kip1 is important for the proliferation and survival of postnatal neurons in the rostal migratory stream and to promote neurogenesis in the developing central nervous system.…”

Section: Cdk4(r/r); P21(+/-); P27(+/-) Cdk4(r/r); P21(-/-); P27(-/-) mentioning

confidence: 99%

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

Quereda

Porlan

Cañamero³

et al. 2015

Cell Death Differ

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Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression. These inhibitors are individually dispensable for the cell cycle and inactivation of specific family members results in increased proliferation and enhanced susceptibility to tumor development. We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21 Cip1 and p27 Kip1 proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors. Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues. Interestingly, complete abrogation of p21 Cip1 and p27 Kip1 in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues. This phenotype correlates with increased replicative stress in developing tissues such as the nervous system and subsequent apoptotic cell death. Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors. We conclude that one of the major physiological activities of cell-cycle inhibitors is to prevent replicative stress during development.

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A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging

Cited by 326 publications

References 47 publications

Replication stress and cancer: It takes two to tango

Replication stress and cancer: It takes two to tango

Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

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