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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-04-01
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| Series: | FEBS Open Bio |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2211-5463.13363 |
| _version_ | 1811297803058544640 |
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| author | Manabu Koike Yasutomo Yutoku Aki Koike |
| author_facet | Manabu Koike Yasutomo Yutoku Aki Koike |
| author_sort | Manabu Koike |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T06:09:34Z |
| format | Article |
| id | doaj.art-31e3d53b75a34ec3a6b723d78e0fdcf7 |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-04-13T06:09:34Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-31e3d53b75a34ec3a6b723d78e0fdcf72022-12-22T02:59:06ZengWileyFEBS Open Bio2211-54632022-04-0112479881010.1002/2211-5463.13363Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sitesManabu Koike0Yasutomo Yutoku1Aki Koike2Institute for Quantum Medical Science National Institutes for Quantum Science and Technology Chiba JapanInstitute for Quantum Medical Science National Institutes for Quantum Science and Technology Chiba JapanInstitute for Quantum Medical Science National Institutes for Quantum Science and Technology Chiba JapanRadiation 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.https://doi.org/10.1002/2211-5463.13363catcompanion animalfelineKu80XRCC4 |
| spellingShingle | Manabu Koike Yasutomo Yutoku Aki Koike Feline XRCC4 undergoes rapid Ku‐dependent recruitment to DNA damage sites FEBS Open Bio cat companion animal feline Ku80 XRCC4 |
| 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 | cat companion animal feline Ku80 XRCC4 |
| url | https://doi.org/10.1002/2211-5463.13363 |
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