The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

Bahassi, El Mustapha; Ovesen, Jerald L.; Riesenberg, Ashley L.; Bernstein, William Z.; Hasty, Paul; Stambrook, Peter J.

doi:10.1038/onc.2008.17

Cited by 147 publications

(120 citation statements)

References 19 publications

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“…Lung appeared to be most affected and mammary tumors less so. That lung tumors were among the most common tumor types in mice with the Chk2*1100delC allele is consistent with the observation that local estrogen levels and ER status may be important in controlling the behavior of some lung tumors and that the ER may be useful as a therapeutic target (43)(44)(45) or as a predictor of disease outcome (46). After treatment with DMBA, mammary tumors and lung tumors were the most increased tumor types.…”

Section: Discussionsupporting

confidence: 54%

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

Bahassi

Robbins²,

Yin³

et al. 2009

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

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The CHEK2 kinase (Chk2 in mouse) is a member of a DNA damage response pathway that regulates cell cycle arrest at cell cycle checkpoints and facilitates the repair of dsDNA breaks by a recombination-mediated mechanism. There are numerous variants of the CHEK2 gene, at least one of which, CHEK2*1100delC (SNP), associates with breast cancer. A mouse model in which the wild-type Chk2 has been replaced by a Chk2*1100delC allele was tested for elevated risk of spontaneous cancer and increased sensitivity to challenge by a carcinogenic compound. Mice homozygous for Chk2*1100delC produced more tumors than wild-type mice, whereas heterozygous mice were not statistically different. When fractionated by gender, however, homozygous and heterozygous mice developed spontaneous tumors more rapidly and to a far greater extent than wild-type mice, indicative of a marked gender bias in mice harboring the variant allele. Consistent with our previous data showing elevated genomic instability in mouse embryonic fibroblasts (MEFs) derived from mice homozygous for Chk2*1100delC, the level of Cdc25A was elevated in heterozygous and homozygous MEFs and tumors. When challenged with the carcinogen 7,12-dimethylbenz[a]anthracene, all mice, regardless of genotype, had a reduced lifespan. Latency for mammary tumorigenesis was reduced significantly in mice homozygous for Chk2*1100delC but unexpectedly increased for the development of lymphomas. An implication from this study is that individuals who harbor the variant CHEK2*1100delC allele not only are at an elevated risk for the development of cancer but also that this risk can be further increased as a result of environmental exposure.cancer predisposition ͉ Cdc25A ͉ polymorphism

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Section: Discussionsupporting

confidence: 54%

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

Bahassi

Robbins²,

Yin³

et al. 2009

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

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“…Phosphorylation of BRCA2 C-terminus by the checkpoint kinases CHK1/CHK2 may also be relevant for BRCA2 function in HR (Fig. 2) (Bahassi et al 2008). Altogether, these findings suggest that the regulation of the function associated with BRCA2 TR2 domain plays a central role in HR-mediated DSB repair.…”

Section: :10supporting

confidence: 52%

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

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“…Once activated by ATR, Chk1 promotes cell-cycle arrest via phosphorylation of Cdc25 phosphatases resulting in their destruction or sequestration, preventing the reversal of inhibitory phosphorylation of the cyclin-dependent kinases (5). Chk1 also inhibits firing of replication origins (6), stabilizes stalled replication forks (7), and regulates proteins involved with DNA repair (8,9). A structurally dissimilar checkpoint kinase, Chk2 is activated by ataxia telangiectasia mutated (ATM) in response to double strand breaks; it promotes both Cdc25 inactivation and p53-dependent cell-cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

The Checkpoint Kinase Inhibitor AZD7762 Potentiates Chemotherapy-Induced Apoptosis of p53-Mutated Multiple Myeloma Cells

Landau

McNeely

Nair

et al. 2012

Molecular Cancer Therapeutics

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DNA cross-linking agents are frequently used in the treatment of multiple myeloma-generating lesions, which activate checkpoint kinase 1 (Chk1), a critical transducer of the DNA damage response. Chk1 activation promotes cell survival by regulating cell-cycle arrest and DNA repair following genotoxic stress. The ability of AZD7762, an ATP-competitive Chk1/2 inhibitor to increase the efficacy of the DNA-damaging agents bendamustine, melphalan, and doxorubicin was examined using four human myeloma cell lines, KMS-12-BM, KMS-12-PE, RPMI-8226, and U266B1. The in vitro activity of AZD7762 as monotherapy and combined with alkylating agents and the "novel" drug bortezomib was evaluated by studying its effects on cytotoxicity, signaling, and apoptotic pathways. The Chk1/2 inhibitor AZD7762 potentiated the antiproliferative effects of bendamustine, melphalan, and doxorubicin but not bortezomib in multiple myeloma cell lines that were p53-deficient. Increased gH2AX staining in cells treated with bendamustine or melphalan plus AZD7762 indicates a greater degree of DNA damage with combined therapy. Abrogation of the G 2 -M checkpoint by AZD7762 resulted in mitotic catastrophe with ensuing apoptosis evidenced by PARP and caspase-3 cleavage. In summary, the cytotoxic effects of bendamustine, melphalan and doxorubicin on p53-deficient multiple myeloma cell lines were enhanced by the coadministration of AZD7762. These data provide a rationale for testing these combinations in patients with relapsed and/or refractory multiple myeloma.

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The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

Cited by 147 publications

References 19 publications

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

BRCA2 functions: from DNA repair to replication fork stabilization

The Checkpoint Kinase Inhibitor AZD7762 Potentiates Chemotherapy-Induced Apoptosis of p53-Mutated Multiple Myeloma Cells

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