DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang, Ruixue; Zhou, Ping‐Kun

doi:10.1038/s41392-020-0150-x

Cited by 673 publications

(500 citation statements)

References 484 publications

(451 reference statements)

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“…They displayed slowly restored appetite, water intake and body weight, as well as gradually disappeared diarrhea ( Figures 1H-J). DNA double-strand breaks (DSBs) are considered as the most lethal form of DNA damage and a primary cause of cell death and are induced by ionizing radiation (IR) during radiotherapy (Huang and Zhou, 2020). Immunohistochemistry was used to detect the proliferation and mitosis of cells in the colorectal samples in our model.…”

Section: Establish a Well-characterized Animal Model Of Radiation-indmentioning

confidence: 99%

Alterations of the Gut Microbiome Composition and Lipid Metabolic Profile in Radiation Enteritis

Yan

Zhang

et al. 2020

Front. Cell. Infect. Microbiol.

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Radiation enteritis (RE) is a common complication in cancer patients receiving radiotherapy. Although studies have shown the changes of this disease at clinical, pathological and other levels, the dynamic characteristics of local microbiome and metabolomics are hitherto unknown. We aimed to examine the multi-omics features of the gut microecosystem, determining the functional correlation between microbiome and lipid metabolites during RE activity. By delivering single high-dose irradiation, a RE mouse model was established. High-throughput 16S rDNA sequencing and global lipidomics analysis were performed to examine microbial and lipidomic profile changes in the gut microecosystem. Spearman correlation analysis was used to determine the functional correlation between bacteria and metabolites. Clinical samples were collected to validate the above observations. During RE activity, the intestinal inflammation of the mice was confirmed by typical signs, symptoms, imaging findings and pathological evidences. 16S datasets revealed that localized irradiation dramatically altered the gut microbial composition, resulting in a decrease ratio of Bacteroidetes to Firmicutes. Lipidomics analysis indicated the remarkable lipidomic profile changes in enteric epithelial barrier, determining that glycerophospholipids metabolism was correlated to RE progression with the highest relevance. Spearman correlation analysis identified that five bacteriametabolite pairs showed the most significant functional correlation in RE, including Alistipes-PC(36:0e), Bacteroides-DG(18:0/20:4), Dubosiella-PC(35:2), Eggerthellaceae-PC(35:6), and Escherichia-Shigella-TG(18:2/18:2/20:4). These observations were partly confirmed in human specimens. Our study provided a comprehensive description of microbiota dysbiosis and lipid metabolic disorders in RE, suggesting strategies to change local microecosystem to relieve radiation injury and maintain homeostasis.

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Section: Establish a Well-characterized Animal Model Of Radiation-indmentioning

confidence: 99%

Alterations of the Gut Microbiome Composition and Lipid Metabolic Profile in Radiation Enteritis

Yan

Zhang

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Therefore, targeting DDR may lead to potentiation of radiotherapy. There are several studies showing the potential of combination therapy based on irradiation and various DDR inhibitors (DNA-dependent protein kinase (DNA-PK), ATM/ATR, LIG4, PARP1, CHK1) but mainly in other types of cancer [197]. Radiotherapy is one of the least used therapeutic methods in OvC treatment at present.…”

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Tomášová

Čumová

Šeborová

et al. 2020

Cancers

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There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.

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“…Sometimes, cancer cells can avoid mitotic arrest and inappropriately enter mitosis before completion of the S and G2 phase; this frequently determines an improper distribution of chromosomes leading to mitotic catastrophe, which is an onco-suppressive signaling cascade preceding cell death via apoptosis, senescence or necrosis, in the first or subsequent cell divisions [101]. Inhibition of proteins that control the S/G2 checkpoint promotes this pathway and in solid cancer this is the main cell death-leading pathway induced by IR treatment [102,103].…”

Section: Targeting Ddc Is One Of the Most Efficient Ways To Tackle Camentioning

confidence: 99%

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

Lodovichi

Cervelli

Pellicioli

et al. 2020

IJMS

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Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

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DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Cited by 673 publications

References 484 publications

Alterations of the Gut Microbiome Composition and Lipid Metabolic Profile in Radiation Enteritis

Alterations of the Gut Microbiome Composition and Lipid Metabolic Profile in Radiation Enteritis

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

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