53BP1/RIF1 signaling promotes cell survival after multifractionated radiotherapy.

Autor:	Eke I; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA., Zong D; Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA., Aryankalayil MJ; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Sandfort V; Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA., Bylicky MA; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Rath BH; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Graves EE; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA., Nussenzweig A; Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA., Coleman CN; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.; Radiation Research Program, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2020 Feb 20; Vol. 48 (3), pp. 1314-1326.
DOI:	10.1093/nar/gkz1139
Abstrakt:	Multifractionated irradiation is the mainstay of radiation treatment in cancer therapy. Yet, little is known about the cellular DNA repair processes that take place between radiation fractions, even though understanding the molecular mechanisms promoting cancer cell recovery and survival could improve patient outcome and identify new avenues for targeted intervention. To address this knowledge gap, we systematically characterized how cells respond differentially to multifractionated and single-dose radiotherapy, using a combination of genetics-based and functional approaches. We found that both cancer cells and normal fibroblasts exhibited enhanced survival after multifractionated irradiation compared with an equivalent single dose of irradiation, and this effect was entirely dependent on 53BP1-mediated NHEJ. Furthermore, we identified RIF1 as the critical effector of 53BP1. Inhibiting 53BP1 recruitment to damaged chromatin completely abolished the survival advantage after multifractionated irradiation and could not be reversed by suppressing excessive end resection. Analysis of the TCGA database revealed lower expression of 53BP1 pathway genes in prostate cancer, suggesting that multifractionated radiotherapy might be a favorable option for radio-oncologic treatment in this tumor type. We propose that elucidation of DNA repair mechanisms elicited by different irradiation dosing regimens could improve radiotherapy selection for the individual patient and maximize the efficacy of radiotherapy. (Published by Oxford University Press on behalf of Nucleic Acids Research 2019.)
Databáze:	MEDLINE
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