BRCA2 mutations predispose carriers to breast and ovarian cancer and can also cause other cancers and Fanconi anemia. BRCA2 acts as a "caretaker" of genome integrity by enabling homologous recombination (HR)-based, error-free DNA double-strand break repair (DSBR) and intra-S phase DNA damage checkpoint control. Described here is the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function.
The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations—misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours.
Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4. TP-064 inhibited the methyltransferase activity of PRMT4 with high potency (half-maximal inhibitory concentration, IC50 < 10 nM) and selectivity over other PRMT family proteins, and reduced arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155; IC50= 340 ± 30 nM) and Mediator complex subunit 12 (MED12; IC50 = 43 ± 10 nM). TP-064 treatment inhibited the proliferation of a subset of multiple myeloma cell lines, with affected cells arrested in G1 phase of the cell cycle. TP-064 and its negative control (TP-064N) will be valuable tools to further investigate the biology of PRMT4 and the therapeutic potential of PRMT4 inhibition.
Background & Aims-Inherited mutations in the BRCA2 tumor suppressor have been associated with an increased risk of pancreatic cancer. To establish the contribution of Brca2 to pancreatic cancer we developed a mouse model of pancreas-specific Brca2 inactivation. Since BRCA2 inactivating mutations cause defects in repair of DNA double-strand breaks that result in chromosomal instability, we evaluated whether Brca2 inactivation induced instability in pancreatic tissue from these mice and whether associated pancreatic tumors were hypersensitive to DNA damaging agents.
Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931–induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS-mutant versus RAS–wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.
The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2⅐FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination.Breast cancer is one of the most common cancers affecting women. About half of all familial cases of breast cancer are caused by mutation in the breast cancer susceptibility genes BRCA1and BRCA2. The BRCA2 gene encodes a 3,418-amino acid protein (1) containing eight conserved BRC motifs (2, 3) through which BRCA2 binds to Rad51, a protein with a crucial role in DNA recombination and repair (4 -6). Because BRCA2 forms a complex with Rad51, a protein directly involved in DNA repair, BRCA2 may link DNA damage signaling pathways with the DNA damage repair machinery.Recent studies indicate that Brca2-defective V-C8 lung fibroblasts are extremely sensitive to DNA cross-linking agents (7). This phenotype is similar to that of Fanconi anemia (FA) 1 cells (8, 9), suggesting that the BRCA2 and FA proteins may function together (10). Fanconi anemia is an autosomal recessive chromosomal disorder (8, 9). There are 11 complementation groups (A, B, C, D1, D2, E, F, G, I, J, and L) (11-13), and 9 of the FA genes have been cloned (A, B, C, D1/BRCA2, D2, E, F, G, and L/PHF9) (8, 9, 13-16). Seven of the proteins (A, B, C, E, F, G, and L) form a nuclear complex and play a role in the mono-ubiquitination of FANCD2 protein in response to DNA damage (16 -21). This modification is required for the repair of DNA cross-links and the accumulation of FANCD2 at the sites of DNA damage (19,22). Recently FANCL/PHF9 was shown to have ubiquitin-protein isopeptide ligase (E3) activity in vitro and to be essential for FANCD2 ubiquitination (14).Recent studies have suggested genetic interactions between FA genes and the breast cancer susceptibility genes BRCA1 an...
Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced nonsmall cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of !1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common EGFR mutations (exon 19 deletions and L858R) and the most potent against cells harboring EGFR-T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common EGFR-G719X, L861Q, and S768I mutations. For recalcitrant EGFR exon 20 insertion mutations, selectivity indexes (wildtype EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors.Implications: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant EGFR mutations.
We describe a new gene (Oogenesin) that is expressed through oogenesis and early embryogenesis in the mouse. De novo expression starts at 15.5 dpc (days postcoitum) in the ovary, which coincides with the start of oogenesis. The isolated cDNA was 1387 base pairs (bp) in length with a single open reading frame of 326 amino acids corresponding to a predicted molecular mass of 37 kDa with no significant homology to previously reported sequences. A remarkable characteristic of the gene is the presence of a leucine zipper structure at amino acid positions 131-152 and a leucine-rich domain at positions 131-254. Northern blot analysis demonstrated that the mRNA was present only in the ovary, in which it was expressed as a single transcript of approximately 1.7 kb. In situ hybridization revealed distinct signals in the oocytes in follicles at all stages (primordial to antral follicles). Western blot analysis demonstrated that the protein is expressed from oocytes to four-cell-stage embryos and that it has a little larger size (46 kDa) than the predicted size of 37. Immunohistochemical analysis of ovary sections revealed that the protein is also expressed specifically in oocytes in follicles at all stages. Furthermore, immunostaining of preimplantation embryos revealed that the protein localizes in nuclei at the late one-cell and early two-cell stages. These results suggest that the gene has some roles in zygotic transcription of early preimplantation embryos as well as folliculogenesis and oogenesis in the mouse.
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