Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure
DNA damage is induced by both endogenous and exogenous factors. Repair of DNA double-strand break (DSB), a serious damage that threatens genome stability, decreases with senescence. However, the molecular mechanisms underlying the decline in DNA repair capacity during senescence remain unclear. We p...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Takashi Oizumi Tomoya Suzuki Junya Kobayashi Asako J. Nakamura |
| author_facet | Takashi Oizumi Tomoya Suzuki Junya Kobayashi Asako J. Nakamura |
| author_sort | Takashi Oizumi |
| collection | DOAJ |
| description | DNA damage is induced by both endogenous and exogenous factors. Repair of DNA double-strand break (DSB), a serious damage that threatens genome stability, decreases with senescence. However, the molecular mechanisms underlying the decline in DNA repair capacity during senescence remain unclear. We performed immunofluorescence staining for phosphorylated histone H2AX (γ-H2AX) in normal human fetal lung fibroblasts and human skin fibroblasts of different ages after chronic irradiation (total dose, 1 Gy; dose rate, 1 Gy/day) to investigate the effect of cellular senescence and organismal aging on DSB repair. Accumulation of DSBs was observed with cellular senescence and organismal aging, probably caused by delayed DSB repair. Importantly, the formation of γ-H2AX foci, an early event in DSB repair, is delayed with cellular senescence and organismal aging. These results suggest that the delay in γ-H2AX focus formation might delay the overall DSB repair. Interestingly, immediate γ-H2AX foci formation was suppressed in cells with senescence-associated heterochromatin foci (SAHF). To investigate the relationship between the γ-H2AX focus formation and SAHF, we used LiCl to relax the SAHFs, followed by irradiation. We demonstrated that LiCl rescued the delayed γ-H2AX foci formation associated with cellular senescence. This indicates that SAHF interferes with γ-H2AX focus formation and inhibits DSB repair in radiation-induced DSB. Our results suggest that therapeutic targeting of SAHFs have potential to resolve DSB repair dysfunction associated with cellular senescence. |
| first_indexed | 2024-04-24T18:11:03Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:03Z |
| publishDate | 2024-03-01 |
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| spelling | doaj.art-226a118d8cd04c5dac058ea7570c48af2024-03-27T13:45:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256335510.3390/ijms25063355Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation ExposureTakashi Oizumi0Tomoya Suzuki1Junya Kobayashi2Asako J. Nakamura3Department of Biological Sciences, College of Science, Ibaraki University, Mito 310-8512, JapanDepartment of Biological Sciences, College of Science, Ibaraki University, Mito 310-8512, JapanSchool of Health Sciences at Narita, International University of Health and Welfare, Chiba 286-8686, JapanDepartment of Biological Sciences, College of Science, Ibaraki University, Mito 310-8512, JapanDNA damage is induced by both endogenous and exogenous factors. Repair of DNA double-strand break (DSB), a serious damage that threatens genome stability, decreases with senescence. However, the molecular mechanisms underlying the decline in DNA repair capacity during senescence remain unclear. We performed immunofluorescence staining for phosphorylated histone H2AX (γ-H2AX) in normal human fetal lung fibroblasts and human skin fibroblasts of different ages after chronic irradiation (total dose, 1 Gy; dose rate, 1 Gy/day) to investigate the effect of cellular senescence and organismal aging on DSB repair. Accumulation of DSBs was observed with cellular senescence and organismal aging, probably caused by delayed DSB repair. Importantly, the formation of γ-H2AX foci, an early event in DSB repair, is delayed with cellular senescence and organismal aging. These results suggest that the delay in γ-H2AX focus formation might delay the overall DSB repair. Interestingly, immediate γ-H2AX foci formation was suppressed in cells with senescence-associated heterochromatin foci (SAHF). To investigate the relationship between the γ-H2AX focus formation and SAHF, we used LiCl to relax the SAHFs, followed by irradiation. We demonstrated that LiCl rescued the delayed γ-H2AX foci formation associated with cellular senescence. This indicates that SAHF interferes with γ-H2AX focus formation and inhibits DSB repair in radiation-induced DSB. Our results suggest that therapeutic targeting of SAHFs have potential to resolve DSB repair dysfunction associated with cellular senescence.https://www.mdpi.com/1422-0067/25/6/3355γ-H2AXDSB repairheterochromatincellular senescence |
| spellingShingle | Takashi Oizumi Tomoya Suzuki Junya Kobayashi Asako J. Nakamura Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure International Journal of Molecular Sciences γ-H2AX DSB repair heterochromatin cellular senescence |
| title | Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure |
| title_full | Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure |
| title_fullStr | Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure |
| title_full_unstemmed | Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure |
| title_short | Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure |
| title_sort | senescence associated heterochromatin foci suppress γ h2ax focus formation induced by radiation exposure |
| topic | γ-H2AX DSB repair heterochromatin cellular senescence |
| url | https://www.mdpi.com/1422-0067/25/6/3355 |
| work_keys_str_mv | AT takashioizumi senescenceassociatedheterochromatinfocisuppressgh2axfocusformationinducedbyradiationexposure AT tomoyasuzuki senescenceassociatedheterochromatinfocisuppressgh2axfocusformationinducedbyradiationexposure AT junyakobayashi senescenceassociatedheterochromatinfocisuppressgh2axfocusformationinducedbyradiationexposure AT asakojnakamura senescenceassociatedheterochromatinfocisuppressgh2axfocusformationinducedbyradiationexposure |