Doxorubicin is one of the most important anti-cancer chemotherapeutic drugs, being widely used for the treatment of solid tumors and acute leukemias. The action of doxorubicin and other anthracycline drugs has been intensively investigated during the last several decades, but the mechanisms that have been proposed for cell killing remain disparate and controversial. In this review, we examine the proposed models for doxorubicin action from the perspective of the chromatin landscape, which is altered in many types of cancer due to recurrent mutations in chromatin modifiers. We highlight recent evidence for effects of anthracyclines on DNA torsion and chromatin dynamics that may underlie basic mechanisms of doxorubicin-mediated cell death and suggest new therapeutic strategies for cancer treatment.
Phycobilisomes (PBSs) are light-harvesting antennae that transfer energy to photosynthetic reaction centers in cyanobacteria and red algae. PBSs are supermolecular complexes composed of phycobiliproteins (PBPs) that bear chromophores for energy absorption and linker proteins. Although the structures of some individual components have been determined using crystallography, the three-dimensional structure of an entire PBS complex, which is critical for understanding the energy transfer mechanism, remains unknown. Here, we report the structures of an intact PBS and a PBS in complex with photosystem II (PSII) from Anabaena sp. strain PCC 7120 using single-particle electron microscopy in combination with biochemical and molecular analyses. In the PBS structure, all PBP trimers and the conserved linker protein domains were unambiguously located, and the global distribution of all chromophores was determined. We provide evidence that ApcE and ApcF are critical for the formation of a protrusion at the bottom of PBS, which plays an important role in mediating PBS interaction with PSII. Our results provide insights into the molecular architecture of an intact PBS at different assembly levels and provide the basis for understanding how the light energy absorbed by PBS is transferred to PSII.
Doxorubicin is an anthracycline DNA intercalator that is among the most commonly used anti-cancer drugs . Doxorubicin causes DNA double-strand breaks in rapidly dividing cells, although whether it also affects general chromatin properties is unknown. Here, we use a metabolic labeling strategy to directly measure nucleosome turnover  to examine the effect of doxorubicin on chromatin dynamics in squamous cell carcinoma cell lines derived from genetically defined mice. We find that doxorubicin enhances nucleosome turnover around gene promoters, and turnover correlates with gene expression level. Consistent with a direct action of doxorubicin, enhancement of nucleosome turnover around promoters gradually increases with time of exposure to the drug. Interestingly, enhancement occurs both in wild-type cells and in cells lacking either the p53 tumor suppressor gene or the master regulator of the DNA damage response, Atm, suggesting that doxorubicin action on nucleosome dynamics is independent of the DNA damage checkpoint. In addition, another anthracycline drug, aclarubicin, shows similar effects on enhancing nucleosome turnover around promoters. Our results suggest that anthracycline intercalation promotes nucleosome turnover around promoters by its effect on DNA topology, with possible implications for mechanisms of cell killing during cancer chemotherapy.
AIM: To i nve s t i g a t e t h e fe a s i b i l i ty o f d e t e c t i n gmethylated fecal DNA as a screening tool for colorectal carcinoma (CRC) and precancerous lesions.
METHODS:Methylated secreted frizzled-related protein gene 2 (SFRP2 ), hyperplastic polyposis protein gene (HPP1 ) and O 6 -methylguanine-DNA methyltransferase gene (MGMT ) in stools from 52 patients with CRC, 35 patients with benign colorectal diseases and 24 normal individuals were analyzed using methylation-specific PCR.RESULTS: Methylated SFRP2 , HPP1 and MGMT were detected in 94.2%, 71.2%, 48.1% of CRC patients and 52.4%, 57.1%, 28.6% of adenoma patients, respectively. The overall prevalence of fecal DNA with at least one methylated gene was 96.2% and 81.8% in patients with CRC and precancerous lesions, respectively. In contrast, only one of the 24 normal individuals revealed methylated DNA. These results indicated a 93.7% sensitivity and a 77.1% specificity of the assay for detecting CRC and precancerous lesions.
CONCLUSION:Methylation testing of fecal DNA using a panel of epigenetic markers may be a simple and promising non-invasive screening method for CRC and precancerous lesions.
Doxorubicin is a widely used chemotherapeutic drug that intercalates
between DNA base-pairs and poisons Topoisomerase II, although the mechanistic
basis for cell killing remains speculative. Doxorubicin and related
anthracycline compounds have been shown to increase nucleosome turnover and/or
eviction around promoters, which suggests that the resulting enhanced exposure
of DNA might underlie cell killing. Previously, we showed that low doses of
anthracyclines increase nucleosome turnover around active gene promoters, which
suggests that loss of nucleosomes might contribute to cancer cell killing. Here
we apply a genome-wide method to precisely map DNA double-strand breaks (DSBs)
in cancer cells. We find that spontaneous DSBs occur preferentially around
promoters of active genes, and that both anthracyclines and etoposide, a
Topoisomerase II poison, increase DSBs around promoters, although CpG islands
are conspicuously protected from DSBs. We propose that torsion-based enhancement
of nucleosome turnover by anthracyclines exposes promoter DNA, ultimately
causing DSBs around promoters.
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