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Role of DNA damage response pathways in preventing carcinogenesis caused by intrinsic replication stress.

Wallace MD, Southard TL, Schimenti KJ, Schimenti JC - Oncogene (2013)

Bottom Line: We found that animals doubly mutant for Chaos3 and components of the ataxia telangiectasia-mutated (ATM) double-strand break response pathway (Atm, p21/Cdkn1a and Chk2/Chek2) had decreased tumor latency and/or increased tumor susceptibility.Tumor latency and susceptibility differed between genetic backgrounds and genders, with females demonstrating an overall greater cancer susceptibility to Atm and p21 deficiency than males.Atm deficiency was semilethal in the Chaos3 background and impaired embryonic fibroblast proliferation, suggesting that ATM drug inhibitors might be useful against tumors with DNA replication defects.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA [2] Department of Molecular Biology and Genetics, Ithaca, NY, USA.

ABSTRACT
Defective DNA replication can result in genomic instability, cancer and developmental defects. To understand the roles of DNA damage response (DDR) genes on carcinogenesis in mutants defective for core DNA replication components, we utilized the Mcm4(Chaos3/Chaos3) ('Chaos3') mouse model that, by virtue of an amino-acid alteration in MCM4 that destabilizes the MCM2-7 DNA replicative helicase, has fewer dormant replication origins and an increased number of stalled replication forks. This leads to genomic instability and cancer in most Chaos3 mice. We found that animals doubly mutant for Chaos3 and components of the ataxia telangiectasia-mutated (ATM) double-strand break response pathway (Atm, p21/Cdkn1a and Chk2/Chek2) had decreased tumor latency and/or increased tumor susceptibility. Tumor latency and susceptibility differed between genetic backgrounds and genders, with females demonstrating an overall greater cancer susceptibility to Atm and p21 deficiency than males. Atm deficiency was semilethal in the Chaos3 background and impaired embryonic fibroblast proliferation, suggesting that ATM drug inhibitors might be useful against tumors with DNA replication defects. Hypomorphism for the 9-1-1 component Hus1 did not affect tumor latency or susceptibility in Chaos3 animals, and tumors in these mice did not exhibit impaired ATR pathway signaling. These and other data indicate that under conditions of systemic replication stress, the ATM pathway is particularly important both for cancer suppression and viability during development.

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Atm deficiency impacts Chaos3 tumor latency and tumor susceptibility(A) DNA damage response pathways. Key genes in DDR pathways are shown with the ATR and ATM DNA damage sensors emphasized in gray boxes. Genes perturbed in this study are indicated by red ovals. (B) Kaplan-Meier graphs of the indicated genotypes and sexes. Mcm4C3/C3 Atm+/− and Mcm4C3/+ Atm+/− females have significantly decreased tumor latency compared to Mcm4C3/C3 alone (see statistics in Supplementary Table 2). Mcm4C3/C3 Atm+/− males neared statistical significance for decreased tumor latency, and Mcm4C3/+ Atm+/− male tumor latency was similar to Mcm4C3/C3 alone (Supplementary Table 2). C3 = Mcm4C3. (C) Tumor spectra of selected genotypes. HS=histiocytic sarcoma, MT=mammary tumor, BT=bone tumor, Ly=lymphoma, None=healthy (no detectable cancer), PCT=plasma cell tumor, RCT=round cell tumor, GCT=granulosa cell tumor, Lv=liver, MH=myeloid hyperplasia, AD=adrenal ganglioneuroma, Un=unknown tumor type. Note that tumor spectrum is affected by genotype and gender, and that Mcm4C3/+ Atm+/− females are more susceptible to cancer than males. C3 = Mcm4C3.
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Figure 1: Atm deficiency impacts Chaos3 tumor latency and tumor susceptibility(A) DNA damage response pathways. Key genes in DDR pathways are shown with the ATR and ATM DNA damage sensors emphasized in gray boxes. Genes perturbed in this study are indicated by red ovals. (B) Kaplan-Meier graphs of the indicated genotypes and sexes. Mcm4C3/C3 Atm+/− and Mcm4C3/+ Atm+/− females have significantly decreased tumor latency compared to Mcm4C3/C3 alone (see statistics in Supplementary Table 2). Mcm4C3/C3 Atm+/− males neared statistical significance for decreased tumor latency, and Mcm4C3/+ Atm+/− male tumor latency was similar to Mcm4C3/C3 alone (Supplementary Table 2). C3 = Mcm4C3. (C) Tumor spectra of selected genotypes. HS=histiocytic sarcoma, MT=mammary tumor, BT=bone tumor, Ly=lymphoma, None=healthy (no detectable cancer), PCT=plasma cell tumor, RCT=round cell tumor, GCT=granulosa cell tumor, Lv=liver, MH=myeloid hyperplasia, AD=adrenal ganglioneuroma, Un=unknown tumor type. Note that tumor spectrum is affected by genotype and gender, and that Mcm4C3/+ Atm+/− females are more susceptible to cancer than males. C3 = Mcm4C3.

Mentions: We generated Chaos3 mice that were also deficient for the ATM pathway (Atm or Chk2), ATR pathway (Hus1), or the cyclin-dependent kinase inhibitor p21 that is downstream of both signaling pathways (Figure 1a). At the time of crossing, Mcm4Chaos3 (abbreviated hereafter as Mcm4C3, or just “C3” in the figures) was congenic in strain C3H/HeBFeJ (C3H), but the other mutations were on different strain backgrounds (see Materials and Methods). C3H-Mcm4C3/C3 females develop exclusively mammary adenocarcinomas, but males of that genotype and strain background were not reported to be tumor prone 19. In a mixed genetic background however, other tumor types in females arise (including lymphoma and histiocytic sarcoma) 19, 25. Additionally, males of mixed strain background were also found to be tumor prone, though the sample size was small and most mice were not aged past 14 months 19. Here, mutant and control mice of both sexes were aged for eighteen months or until they showed signs of disease, after which a complete necropsy was performed. The results for each set of compound mutants are described below.


Role of DNA damage response pathways in preventing carcinogenesis caused by intrinsic replication stress.

Wallace MD, Southard TL, Schimenti KJ, Schimenti JC - Oncogene (2013)

Atm deficiency impacts Chaos3 tumor latency and tumor susceptibility(A) DNA damage response pathways. Key genes in DDR pathways are shown with the ATR and ATM DNA damage sensors emphasized in gray boxes. Genes perturbed in this study are indicated by red ovals. (B) Kaplan-Meier graphs of the indicated genotypes and sexes. Mcm4C3/C3 Atm+/− and Mcm4C3/+ Atm+/− females have significantly decreased tumor latency compared to Mcm4C3/C3 alone (see statistics in Supplementary Table 2). Mcm4C3/C3 Atm+/− males neared statistical significance for decreased tumor latency, and Mcm4C3/+ Atm+/− male tumor latency was similar to Mcm4C3/C3 alone (Supplementary Table 2). C3 = Mcm4C3. (C) Tumor spectra of selected genotypes. HS=histiocytic sarcoma, MT=mammary tumor, BT=bone tumor, Ly=lymphoma, None=healthy (no detectable cancer), PCT=plasma cell tumor, RCT=round cell tumor, GCT=granulosa cell tumor, Lv=liver, MH=myeloid hyperplasia, AD=adrenal ganglioneuroma, Un=unknown tumor type. Note that tumor spectrum is affected by genotype and gender, and that Mcm4C3/+ Atm+/− females are more susceptible to cancer than males. C3 = Mcm4C3.
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Figure 1: Atm deficiency impacts Chaos3 tumor latency and tumor susceptibility(A) DNA damage response pathways. Key genes in DDR pathways are shown with the ATR and ATM DNA damage sensors emphasized in gray boxes. Genes perturbed in this study are indicated by red ovals. (B) Kaplan-Meier graphs of the indicated genotypes and sexes. Mcm4C3/C3 Atm+/− and Mcm4C3/+ Atm+/− females have significantly decreased tumor latency compared to Mcm4C3/C3 alone (see statistics in Supplementary Table 2). Mcm4C3/C3 Atm+/− males neared statistical significance for decreased tumor latency, and Mcm4C3/+ Atm+/− male tumor latency was similar to Mcm4C3/C3 alone (Supplementary Table 2). C3 = Mcm4C3. (C) Tumor spectra of selected genotypes. HS=histiocytic sarcoma, MT=mammary tumor, BT=bone tumor, Ly=lymphoma, None=healthy (no detectable cancer), PCT=plasma cell tumor, RCT=round cell tumor, GCT=granulosa cell tumor, Lv=liver, MH=myeloid hyperplasia, AD=adrenal ganglioneuroma, Un=unknown tumor type. Note that tumor spectrum is affected by genotype and gender, and that Mcm4C3/+ Atm+/− females are more susceptible to cancer than males. C3 = Mcm4C3.
Mentions: We generated Chaos3 mice that were also deficient for the ATM pathway (Atm or Chk2), ATR pathway (Hus1), or the cyclin-dependent kinase inhibitor p21 that is downstream of both signaling pathways (Figure 1a). At the time of crossing, Mcm4Chaos3 (abbreviated hereafter as Mcm4C3, or just “C3” in the figures) was congenic in strain C3H/HeBFeJ (C3H), but the other mutations were on different strain backgrounds (see Materials and Methods). C3H-Mcm4C3/C3 females develop exclusively mammary adenocarcinomas, but males of that genotype and strain background were not reported to be tumor prone 19. In a mixed genetic background however, other tumor types in females arise (including lymphoma and histiocytic sarcoma) 19, 25. Additionally, males of mixed strain background were also found to be tumor prone, though the sample size was small and most mice were not aged past 14 months 19. Here, mutant and control mice of both sexes were aged for eighteen months or until they showed signs of disease, after which a complete necropsy was performed. The results for each set of compound mutants are described below.

Bottom Line: We found that animals doubly mutant for Chaos3 and components of the ataxia telangiectasia-mutated (ATM) double-strand break response pathway (Atm, p21/Cdkn1a and Chk2/Chek2) had decreased tumor latency and/or increased tumor susceptibility.Tumor latency and susceptibility differed between genetic backgrounds and genders, with females demonstrating an overall greater cancer susceptibility to Atm and p21 deficiency than males.Atm deficiency was semilethal in the Chaos3 background and impaired embryonic fibroblast proliferation, suggesting that ATM drug inhibitors might be useful against tumors with DNA replication defects.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA [2] Department of Molecular Biology and Genetics, Ithaca, NY, USA.

ABSTRACT
Defective DNA replication can result in genomic instability, cancer and developmental defects. To understand the roles of DNA damage response (DDR) genes on carcinogenesis in mutants defective for core DNA replication components, we utilized the Mcm4(Chaos3/Chaos3) ('Chaos3') mouse model that, by virtue of an amino-acid alteration in MCM4 that destabilizes the MCM2-7 DNA replicative helicase, has fewer dormant replication origins and an increased number of stalled replication forks. This leads to genomic instability and cancer in most Chaos3 mice. We found that animals doubly mutant for Chaos3 and components of the ataxia telangiectasia-mutated (ATM) double-strand break response pathway (Atm, p21/Cdkn1a and Chk2/Chek2) had decreased tumor latency and/or increased tumor susceptibility. Tumor latency and susceptibility differed between genetic backgrounds and genders, with females demonstrating an overall greater cancer susceptibility to Atm and p21 deficiency than males. Atm deficiency was semilethal in the Chaos3 background and impaired embryonic fibroblast proliferation, suggesting that ATM drug inhibitors might be useful against tumors with DNA replication defects. Hypomorphism for the 9-1-1 component Hus1 did not affect tumor latency or susceptibility in Chaos3 animals, and tumors in these mice did not exhibit impaired ATR pathway signaling. These and other data indicate that under conditions of systemic replication stress, the ATM pathway is particularly important both for cancer suppression and viability during development.

Show MeSH
Related in: MedlinePlus