Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments
Abstract Tumor suppressor p53 plays a central role in response to DNA damage. DNA-damaging agents modulate nuclear actin dynamics, influencing cell behaviors; however, whether p53 affects the formation of nuclear actin filaments remains unclear. In this study, we found that p53 depletion promoted th...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06310-0 |
| _version_ | 1827632938367320064 |
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| author | Takeru Torii Wataru Sugimoto Katsuhiko Itoh Natsuki Kinoshita Masaya Gessho Toshiyuki Goto Ikuno Uehara Wataru Nakajima Yemima Budirahardja Daisuke Miyoshi Takahito Nishikata Nobuyuki Tanaka Hiroaki Hirata Keiko Kawauchi |
| author_facet | Takeru Torii Wataru Sugimoto Katsuhiko Itoh Natsuki Kinoshita Masaya Gessho Toshiyuki Goto Ikuno Uehara Wataru Nakajima Yemima Budirahardja Daisuke Miyoshi Takahito Nishikata Nobuyuki Tanaka Hiroaki Hirata Keiko Kawauchi |
| author_sort | Takeru Torii |
| collection | DOAJ |
| description | Abstract Tumor suppressor p53 plays a central role in response to DNA damage. DNA-damaging agents modulate nuclear actin dynamics, influencing cell behaviors; however, whether p53 affects the formation of nuclear actin filaments remains unclear. In this study, we found that p53 depletion promoted the formation of nuclear actin filaments in response to DNA-damaging agents, such as doxorubicin (DOXO) and etoposide (VP16). Even though the genetic probes used for the detection of nuclear actin filaments exerted a promotive effect on actin polymerization, the detected formation of nuclear actin filaments was highly dependent on both p53 depletion and DNA damage. Whilst active p53 is known to promote caspase-1 expression, the overexpression of caspase-1 reduced DNA damage-induced formation of nuclear actin filaments in p53-depleted cells. In contrast, co-treatment with DOXO and the pan-caspase inhibitor Q-VD-OPh or the caspase-1 inhibitor Z-YVAD-FMK induced the formation of nuclear actin filament formation even in cells bearing wild-type p53. These results suggest that the p53-caspase-1 axis suppresses DNA damage-induced formation of nuclear actin filaments. In addition, we found that the expression of nLifeact-GFP, the filamentous-actin-binding peptide Lifeact fused with the nuclear localization signal (NLS) and GFP, modulated the structure of nuclear actin filaments to be phalloidin-stainable in p53-depleted cells treated with the DNA-damaging agent, altering the chromatin structure and reducing the transcriptional activity. The level of phosphorylated H2AX (γH2AX), a marker of DNA damage, in these cells also reduced upon nLifeact-GFP expression, whilst details of the functional relationship between the formation of nLifeact-GFP-decorated nuclear actin filaments and DNA repair remained to be elucidated. Considering that the loss of p53 is associated with cancer progression, the results of this study raise a possibility that the artificial reinforcement of nuclear actin filaments by nLifeact-GFP may enhance the cytotoxic effect of DNA-damaging agents in aggressive cancer cells through a reduction in gene transcription. |
| first_indexed | 2024-03-09T14:52:35Z |
| format | Article |
| id | doaj.art-b843a706f4784b80a940b74af021a3d9 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-09T14:52:35Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-b843a706f4784b80a940b74af021a3d92023-11-26T14:22:53ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141111010.1038/s41419-023-06310-0Loss of p53 function promotes DNA damage-induced formation of nuclear actin filamentsTakeru Torii0Wataru Sugimoto1Katsuhiko Itoh2Natsuki Kinoshita3Masaya Gessho4Toshiyuki Goto5Ikuno Uehara6Wataru Nakajima7Yemima Budirahardja8Daisuke Miyoshi9Takahito Nishikata10Nobuyuki Tanaka11Hiroaki Hirata12Keiko Kawauchi13Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical SchoolDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical SchoolFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical SchoolDepartment of Applied Bioscience, Kanazawa Institute of TechnologyFaculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan UniversityAbstract Tumor suppressor p53 plays a central role in response to DNA damage. DNA-damaging agents modulate nuclear actin dynamics, influencing cell behaviors; however, whether p53 affects the formation of nuclear actin filaments remains unclear. In this study, we found that p53 depletion promoted the formation of nuclear actin filaments in response to DNA-damaging agents, such as doxorubicin (DOXO) and etoposide (VP16). Even though the genetic probes used for the detection of nuclear actin filaments exerted a promotive effect on actin polymerization, the detected formation of nuclear actin filaments was highly dependent on both p53 depletion and DNA damage. Whilst active p53 is known to promote caspase-1 expression, the overexpression of caspase-1 reduced DNA damage-induced formation of nuclear actin filaments in p53-depleted cells. In contrast, co-treatment with DOXO and the pan-caspase inhibitor Q-VD-OPh or the caspase-1 inhibitor Z-YVAD-FMK induced the formation of nuclear actin filament formation even in cells bearing wild-type p53. These results suggest that the p53-caspase-1 axis suppresses DNA damage-induced formation of nuclear actin filaments. In addition, we found that the expression of nLifeact-GFP, the filamentous-actin-binding peptide Lifeact fused with the nuclear localization signal (NLS) and GFP, modulated the structure of nuclear actin filaments to be phalloidin-stainable in p53-depleted cells treated with the DNA-damaging agent, altering the chromatin structure and reducing the transcriptional activity. The level of phosphorylated H2AX (γH2AX), a marker of DNA damage, in these cells also reduced upon nLifeact-GFP expression, whilst details of the functional relationship between the formation of nLifeact-GFP-decorated nuclear actin filaments and DNA repair remained to be elucidated. Considering that the loss of p53 is associated with cancer progression, the results of this study raise a possibility that the artificial reinforcement of nuclear actin filaments by nLifeact-GFP may enhance the cytotoxic effect of DNA-damaging agents in aggressive cancer cells through a reduction in gene transcription.https://doi.org/10.1038/s41419-023-06310-0 |
| spellingShingle | Takeru Torii Wataru Sugimoto Katsuhiko Itoh Natsuki Kinoshita Masaya Gessho Toshiyuki Goto Ikuno Uehara Wataru Nakajima Yemima Budirahardja Daisuke Miyoshi Takahito Nishikata Nobuyuki Tanaka Hiroaki Hirata Keiko Kawauchi Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments Cell Death and Disease |
| title | Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments |
| title_full | Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments |
| title_fullStr | Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments |
| title_full_unstemmed | Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments |
| title_short | Loss of p53 function promotes DNA damage-induced formation of nuclear actin filaments |
| title_sort | loss of p53 function promotes dna damage induced formation of nuclear actin filaments |
| url | https://doi.org/10.1038/s41419-023-06310-0 |
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