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Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites

Radiation and chemotherapy resistance remain some of the greatest challenges in human and veterinary cancer therapies. XRCC4, an essential molecule for nonhomologous end joining repair, is a promising target for radiosensitizers. Genetic variants and mutations of XRCC4 contribute to cancer susceptib...

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Autores principales: Koike, Manabu, Yutoku, Yasutomo, Koike, Aki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972062/
https://www.ncbi.nlm.nih.gov/pubmed/35000298
http://dx.doi.org/10.1002/2211-5463.13363
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author Koike, Manabu
Yutoku, Yasutomo
Koike, Aki
author_facet Koike, Manabu
Yutoku, Yasutomo
Koike, Aki
author_sort Koike, Manabu
collection PubMed
description Radiation and chemotherapy resistance remain some of the greatest challenges in human and veterinary cancer therapies. XRCC4, an essential molecule for nonhomologous end joining repair, is a promising target for radiosensitizers. Genetic variants and mutations of XRCC4 contribute to cancer susceptibility, and XRCC4 is also the causative gene of microcephalic primordial dwarfism (MPD) in humans. The development of clinically effective molecular‐targeted drugs requires accurate understanding of the functions and regulatory mechanisms of XRCC4. In this study, we cloned and sequenced the cDNA of feline XRCC4. Comparative analysis indicated that sequences and post‐translational modification sites that are predicted to be involved in regulating the localization of human XRCC4, including the nuclear localization signal, are mostly conserved in feline XRCC4. All examined target amino acids responsible for human MPD are completely conserved in feline XRCC4. Furthermore, we found that the localization of feline XRCC4 dynamically changes during the cell cycle. Soon after irradiation, feline XRCC4 accumulated at laser‐induced DNA double‐strand break (DSB) sites in both the interphase and mitotic phase, and this accumulation was dependent on the presence of Ku. Additionally, XRCC4 superfamily proteins XLF and PAXX accumulated at the DSB sites. Collectively, these findings suggest that mechanisms regulating the spatiotemporal localization of XRCC4 are crucial for XRCC4 function in humans and cats. Our findings contribute to elucidating the functions of XRCC4 and the role of abnormal XRCC4 in diseases, including cancers and MPD, and may help in developing XRCC4‐targeted drugs, such as radiosensitizers, for humans and cats.
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spelling pubmed-89720622022-04-05 Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites Koike, Manabu Yutoku, Yasutomo Koike, Aki FEBS Open Bio Research Articles Radiation and chemotherapy resistance remain some of the greatest challenges in human and veterinary cancer therapies. XRCC4, an essential molecule for nonhomologous end joining repair, is a promising target for radiosensitizers. Genetic variants and mutations of XRCC4 contribute to cancer susceptibility, and XRCC4 is also the causative gene of microcephalic primordial dwarfism (MPD) in humans. The development of clinically effective molecular‐targeted drugs requires accurate understanding of the functions and regulatory mechanisms of XRCC4. In this study, we cloned and sequenced the cDNA of feline XRCC4. Comparative analysis indicated that sequences and post‐translational modification sites that are predicted to be involved in regulating the localization of human XRCC4, including the nuclear localization signal, are mostly conserved in feline XRCC4. All examined target amino acids responsible for human MPD are completely conserved in feline XRCC4. Furthermore, we found that the localization of feline XRCC4 dynamically changes during the cell cycle. Soon after irradiation, feline XRCC4 accumulated at laser‐induced DNA double‐strand break (DSB) sites in both the interphase and mitotic phase, and this accumulation was dependent on the presence of Ku. Additionally, XRCC4 superfamily proteins XLF and PAXX accumulated at the DSB sites. Collectively, these findings suggest that mechanisms regulating the spatiotemporal localization of XRCC4 are crucial for XRCC4 function in humans and cats. Our findings contribute to elucidating the functions of XRCC4 and the role of abnormal XRCC4 in diseases, including cancers and MPD, and may help in developing XRCC4‐targeted drugs, such as radiosensitizers, for humans and cats. John Wiley and Sons Inc. 2022-02-18 /pmc/articles/PMC8972062/ /pubmed/35000298 http://dx.doi.org/10.1002/2211-5463.13363 Text en © 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Koike, Manabu
Yutoku, Yasutomo
Koike, Aki
Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites
title Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites
title_full Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites
title_fullStr Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites
title_full_unstemmed Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites
title_short Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites
title_sort feline xrcc4 undergoes rapid ku‐dependent recruitment to dna damage sites
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972062/
https://www.ncbi.nlm.nih.gov/pubmed/35000298
http://dx.doi.org/10.1002/2211-5463.13363
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