In their natural habitat of rotting fruit, the nematode feeds on the complex bacterial communities that thrive in this rich growth medium. Hundreds of diverse bacterial strains cultured from such rotting fruit allow growth and reproduction when tested individually. In screens for responses to single bacterial strains associated with nematodes in fruit, we found that causes a genome instability phenotype; we observed abnormally long or fragmented intestinal nuclei due to aberrant nuclear division, or defective karyokinesis. The karyokinesis defects were restricted to intestinal cells and required close proximity between bacteria and the worm. A genetic screen for mutations that cause the same intestinal karyokinesis defect followed by genome sequencing of the isolated mutant strains identified mutations that disrupt DNA damage repair pathways, suggesting that may cause DNA damage in intestinal cells. We hypothesized that such DNA damage is caused by reactive oxygen species produced by and found that hydrogen peroxide added to benign can cause the same intestinal karyokinesis defects in WT Supporting this model, free radical scavengers suppressed the -induced DNA damage. Thus, may signal to eukaryotic hosts via reactive oxygen species, and the host may respond with DNA damage repair pathways.
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http://dx.doi.org/10.1073/pnas.1815656116 | DOI Listing |
Nat Commun
January 2025
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi.
View Article and Find Full Text PDFCurr Cancer Drug Targets
January 2025
Cancer Research Center, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
Among the Poly(ADP-ribose) Polymerase (PARP) family in mammals, PARP1 is the first identified and well-studied member that plays a critical role in DNA damage repair and has been proven to be an effective target for cancer therapy. Here, we have reviewed not only the role of PARP1 in different DNA damage repair pathways, but also the working mechanisms of several PARP inhibitors (PARPi), inhibiting Poly-ADP-ribosylation (PARylation) processing and PAR chains production to trap PARP1 on impaired DNA and inducing Transcription- replication Conflicts (TRCs) by inhibiting the PARP1 activity. This review has systematically summarized the latest clinical application of six authorized PARPi, including olaparib, rucaparib, niraparib, talazoparib, fuzuloparib and pamiparib, in monotherapy and combination therapies with chemotherapy, radiotherapy, and immunotherapy, in different kinds of cancer.
View Article and Find Full Text PDFJ Cell Mol Med
January 2025
Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.
Bladder cancer originates from bladder tissues and is the ninth most common type of cancer worldwide. The SWI/SNF (SWItch/sucrose non- fermentable) complex plays a crucial role in regulating various biological processes, such as cell cycle control, DNA damage repair and transcription regulation. The purpose of this article is to examine the functional studies of the SWI/SNF complex in bladder cancer, highlighting new pathways for creating personalised treatment approaches for bladder cancer patients with mutations in the SWI/SNF complex.
View Article and Find Full Text PDFNucleic Acids Res
January 2025
Oxidative Stress Group, Department of Molecular Biosciences, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620, USA.
Most of the risk factors associated with chronic and complex diseases, such as cancer, stem from exogenous and endogenous exposures experienced throughout an individual's life, collectively known as the exposome. These exposures can modify DNA, which can subsequently lead to the somatic mutations found in all normal and tumor tissues. Understanding the precise origins of specific somatic mutations has been challenging due to multitude of DNA adducts (i.
View Article and Find Full Text PDFNucleic Acids Res
January 2025
Korea Bioinformation Center, Korea Research Institute of Bioscience & Biotechnology, 125, Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
Given the presence of highly repetitive genomic regions such as subtelomeric regions, understanding human genomic evolution remains challenging. Recently, long-read sequencing technology has facilitated the identification of complex genetic variants, including structural variants (SVs), at the single-nucleotide level. Here, we resolved SVs and their underlying DNA damage-repair mechanisms in subtelomeric regions, which are among the most uncharted genomic regions.
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