[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-332961-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-332961-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","enhancing-low-dose-radiotherapy-efficacy-with-parp-inhibitors-via-fbl-mediated-oxidative-stress-response-in-colorectal-cancer","Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer","","Radiotherapy effectiveness in colorectal cancer depends on reactive oxygen species–driven cell death, yet oxidative stress–mitigating genes can blunt treatment response. This study links the nucleolar protein Fibrillarin (FBL) with oxidative stress response in CRC tumors, showing elevated FBL expression correlated with oxidative stress levels. Mechanistically, PARP1-regulated FBL accumulates at DNA damage sites, promoting short-patch base excision repair and altering DNA damage burdens. Tumors with high FBL exhibit reduced DNA damage and increased sensitivity to combined low-dose radiotherapy and olaparib, supporting PARP inhibitors as a strategy to enhance radiotherapy sensitivity in selected CRC.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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does low-dose radiotherapy kill colorectal cancer cells?","Question",{"text":63,"@type":64},"Low-dose radiotherapy induces cell death primarily by generating reactive oxygen species (ROS) and causing DNA damage that exceeds the cell’s repair capacity.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What role does Fibrillarin (FBL) play in CRC oxidative stress response?",{"text":68,"@type":64},"FBL expression is elevated in colorectal cancer and positively correlates with oxidative stress levels, linking it to the oxidative stress response in CRC tumors.",{"name":70,"@type":61,"acceptedAnswer":71},"Why does combining PARP inhibition with low-dose radiotherapy increase sensitivity?",{"text":72,"@type":64},"Mechanistically, PARP1-regulated accumulation of damaged FBL supports short-patched base excision repair, and tumors with higher FBL show reduced DNA damage while becoming more sensitive to combined low-dose radiotherapy and olaparib.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},332961,1790174263,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,111,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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Oncogene)[ Oncogene](www.nature.com/onc Oncogene)  \nARTICLE OPEN   \nEnhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer  \nMing Wen1,2,3,4,5,13, Yanfang Qiu 1,2,6,13, Meng Wang1,2, Feiyu Tang 1,2, Wenfeng Hu1,2, Yongwei Zhu7, Wenchao Zhao1,2, Wenzhen Hu 1,2, Zhuohang Chen 1,2, Yumei Duan8, Anke Geng9, Fengbo Tan10, Yuqiang Li10, Qian Pei10, Haiping Pei 10, Zhiyong Mao 9, Ningbo Wu11, Lunquan Sun 1,2,3,4,5 ✉ and Rong Tan 1,2,3,4,5,12 ✉  \n© The Author(s) 2024  \nThe effectiveness of radiotherapy in colorectal cancer (CRC) relies on its ability to induce cell death via the generation of reactive oxygen species (ROS) . However, genes responsible for mitigating oxidative stress can impede radiotherapy’s efficacy. In this study, we elucidate a significant association between the nucleolar protein Fibrillarin (FBL) and the oxidative stress response in CRC tumors. Our findings reveal elevated expression of FBL in colorectal cancer, which positively correlates with oxidative stress levels. Mechanistically, FBL demonstrates direct accumulation at DNA damage sites under the regulation of PARP1 . Specifically, the N-terminal GAR domain of FBL is susceptible to PARylation by PARP1, enabling FBL to recognize PARylated proteins. The accumulation of damaged FBL plays a pivotal role in facilitating short-patched base excision repair by recruiting Ligase III and disassociating PCNA and FEN1 . Moreover, tumors with heightened FBL expression exhibit reduced DNA damage levels but increased sensitivity to combined low-dose radiotherapy and olaparib treatment. This underscores the potential of leveraging PARP inhibitors to augment radiotherapy sensitivity in CRC cases characterized by elevated FBL expression, offering a promising therapeutic avenue.  \nOncogene (2025) 44:228–240; [https://doi.org/10.1038/s41388-024-03207-w](https://doi.org/10.1038/s41388-024-03207-w)  \nINTRODUCTION  \nChemoradiotherapy is widely employed as a preoperative intervention for advanced rectal cancer, yet a significant proportion of patients, approximately 75%–80%, do not attain complete responses [1, 2] . This highlights the urgent need for precisionbased strategies to enhance therapeutic outcomes in specific patient subsets. Radiotherapy eradicates cancer cells by producing reactive oxygen species (ROS) and inflicting DNA damage beyond the cell’s repair capability. Consequently, identification of targets that mitigate oxidative stress could offer crucial insights into the mechanisms underlying radioresistance.  \nThe intestine is characterized by its resident gut microbiota, active metabolism, and persistent inflammatory stresses. Oxidative stress, which stems from inflammation, high metabolic activity, and various internal and external factors, is recognized as a key threat to genomic integrity [3, 4] . Elevated levels of reactive oxygen species (ROS) preferentially target guanine-rich sequencesin the genome, resulting in oxidized base lesions such as 8-oxo- 7,8-dihydro-2’-deoxyguanosine (8-oxodG) or 8-hydroxy-2’-  \ndeoxyguanosine (8-OHdG). These lesions are detected and excised by oxidative DNA damage response (DDR) mechanisms and subsequently repaired through the base excision repair (BER) pathway. However, when oxidative damage surpasses the BER pathway’s repair capacity, it can lead to the formation of singlestrand or double-strand DNA breaks. The role of oxidative damage and the homeostasis of DNA damage repair in radiotherapeutic  \nefficacy in colorectal cancer (CRC) is still not fully understood.  \nPARP1 is an enzyme with crucial roles in DNA damage repair and gene regulation. Upon DNA damage, PARP1 can be activated by damaged DNA, subsequently amplifying signal pathways by recruiting various substrates through poly(ADP-ribosyl)ation (PARylation). PARP inhibitors (PARPis) were initially identified as effective targets in ovarian and breast cancers with homologous reco","cbCaibZS2zxH9QYG","https://ap.wps.com/l/cbCaibZS2zxH9QYG","pdf",5804879,13,"English","# Introduction\n## Oxidative stress and DNA damage response in CRC\n## PARP1, PARylation, and PARP inhibitors in radiosensitization","[{\"question\":\"How does low-dose radiotherapy kill colorectal cancer cells?\",\"answer\":\"Low-dose radiotherapy induces cell death primarily by generating reactive oxygen species (ROS) and causing DNA damage that exceeds the cell’s repair capacity.\"},{\"question\":\"What role does Fibrillarin (FBL) play in CRC oxidative stress response?\",\"answer\":\"FBL expression is elevated in colorectal cancer and positively correlates with oxidative stress levels, linking it to the oxidative stress response in CRC tumors.\"},{\"question\":\"Why does combining PARP inhibition with low-dose radiotherapy increase sensitivity?\",\"answer\":\"Mechanistically, PARP1-regulated accumulation of damaged FBL supports short-patched base excision repair, and tumors with higher FBL show reduced DNA damage while becoming more sensitive to combined low-dose radiotherapy and olaparib.\"}]","Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer | PDF",1790000168,33]