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PARPi focus the spotlight on replication fork protection in cancer

Nature Cell Biology 19, 1309 (2017). doi:10.1038/ncb3638 Author: Katharina Schlacher PARP inhibitors (PARPi) kill BRCA1/2-mutated cancers, which become resistant when DNA repair functions are restored. Now, MUS81 nuclease inhibition due to EZH2 downregulation is found to restore DNA replication fork protection but not repair, leading to PARPi-resistance in mutant BRCA2 cells and patients. This challenges the DNA repair dominance in synthetic lethality.
Source: Nature Cell Biology - Category: Cytology Authors: Tags: News and Views Source Type: research

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Authors: Sabatucci I, Maltese G, Lepori S, Tripodi E, Bogani G, Lorusso D Abstract INTRODUCTION: Approximately 50% of high-grade serous ovarian cancers present a deficiency in the pathways involved in homologous recombination (HR). PARP inhibitors prevent single-strand DNA damage repair and determine a progression of the defect towards double-strand breaks, which results in a process known as 'synthetic lethality'. Areas covered: In this review, the authors discuss the efficacy and toxicity of rucaparib either as a single agent or as a maintenance treatment for ovarian cancer. This includes the NGS Foundation Medic...
Source: Expert Opinion on Pharmacotherapy - Category: Drugs & Pharmacology Tags: Expert Opin Pharmacother Source Type: research
Antagonistic pleiotropy is the name given to the phenomenon in which evolutionary processes select for a genetic variant that aids in evolutionary fitness when young, but then causes harm to the individual later in life. Many theorists consider aging as a whole to be antagonistic pleiotropy writ large, but one can pick out individual mechanisms in many species that are compelling candidates to be the result of such a process. In the open access paper noted here, the authors point out one plausibly pleiotropic set of genes in our species. Expansion of gene families with the concomitant acquisition of new functions ...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs
ConclusionsI identified several genes that are co-mutated in primary KRAS-mutant lung cancer samples. I also identified subpopulations of KRAS-mutant lung cancers based on sets of genes that were co-mutated. Pre-clinical models that capture these subsets of KRAS-mutant tumors may enhance our understanding of lung cancer development and, in addition, facilitate the design of personalized treatment strategies for lung cancer patients carrying KRAS mutations.
Source: Cellular Oncology - Category: Cancer & Oncology Source Type: research
Previously, we found genistein could sensitize cancer cells to low linear energy transfer (LET) X-rays via inhibiting DNA-PKcs activities. Especially, high-LET heavy ion produces more DNA double strand breaks (DSBs) than low-LET radiation. Thus, the study was designed to investigate the detailed molecular mechanisms of genistein on sensitizing cancer cells to heavy ions.
Source: Radiotherapy and Oncology - Category: Radiology Authors: Source Type: research
In conclusion, this study provides evidence to support the theory that DNA repair genes are associated with breast cancer risk, providing information to further understand breast cancer etiology. and The potential biological pathways linking DNA repair, ethnic background, environment and breast cancer require further investigation. PMID: 29662639 [PubMed]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
This article originally appeared on Health.com
Source: TIME: Health - Category: Consumer Health News Authors: Tags: Uncategorized Diet/Nutrition healthytime onetime Source Type: news
Xeroderma pigmentosum is a rare genetic disease characterized by a severe susceptibility to cutaneous cancers (CC). This disease is due to defective nucleotide excision repair of DNA lesions occurring upon solar radiation. XP patients are prone to particularly aggressive CC as compared to the general population. Evidence supports the role of the activation of tumor microenvironment by cancer cells, notably on dermal fibroblasts that, in turn, fuel the growth of aggressive cancers. We hypothesized that XP fibroblasts could influence cancer types in XP patients.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Carcinogenesis and Cancer Genetics Source Type: research
Hematologic abnormalities are rarely reported in xeroderma pigmentosum (XP). XP, a rare genodermatosis with a 10,000-fold increased risk for skin and ocular cancers, is caused by an inability to repair UV induced DNA damage. Improved disease management has resulted in XP patients living longer and developing conditions associated with premature aging (early menopause and internal malignancies). A 19 yr Moroccan girl, XP540BE, with homozygous mutations in XPC, was seen at NIH under a natural history protocol.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Carcinogenesis and Cancer Genetics Source Type: research
Many antioxidants inhibit immune suppression and/or skin cancer formation in experimental animals exposed to UVB (280-320 nm) radiation. In this regard, PT has been shown to protect hairless mice against UVB radiation-induced skin damage and carcinogenesis. Nicotinamide has been shown to enhance and repair UVB-induced DNA damage in a transformed human keratinocyte line and in human skin ex vivo as well as in primary melanocytes. It also downregulates expression of some inflammatory peptides including IL-6, IL-10, monocyte chemoattractant protein 1 and tumor necrosis factor alpha in transformed human keratinocytes exposed to UVB radiation.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Photobiology Source Type: research
Mutations in the XPA gene give rise to the most severe form of XP, a disease characterized by UV hypersensitivity, a dramatically increased skin cancer risk, and progeroid features. This phenotype is primarily attributed to a defect in nucleotide excision repair (NER), but recent studies indicate a role of XPA beyond NER. Accordingly, XPA deficient fibroblasts (XPA-F) exhibit mitochondrial dysfunction including disturbed mitophagy and enhanced ATP depletion. Persistent mitochondrial dysfunction may trigger the secretion of a pattern of soluble factors, which was first described in senescent cells and for which the term SASP was coined.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Photobiology Source Type: research
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