Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells
We investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cance...
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| Format: | Article |
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/11/9530 |
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| author | Hani Lee Sojung Ha SeokGyeong Choi Soomin Do Sukjoon Yoon Yong Kee Kim Woo-Young Kim |
| author_facet | Hani Lee Sojung Ha SeokGyeong Choi Soomin Do Sukjoon Yoon Yong Kee Kim Woo-Young Kim |
| author_sort | Hani Lee |
| collection | DOAJ |
| description | We investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cancer stem cell (CSC)-enriched cultures and bulk/general mixed cell cultures (BCCs) with RNAi were employed to determine the effect of <i>TONSL</i> loss in cancer cell lines from the ovary, breast, stomach, lung, colon and brain. Limited dilution assays and ALDH assays were used to quantify the loss of CSCs. Western blotting and cell-based homologous recombination assays were used to identify DNA damage derived from TONSL loss. <i>TONSL</i> was expressed at higher levels in cancer tissues than in normal tissues, and higher expression was an unfavorable prognostic marker for lung, stomach, breast and ovarian cancers. Higher expression of <i>TONSL</i> is partly associated with the coamplification of <i>TONSL</i> and <i>MYC</i>, suggesting its oncogenic role. The suppression of <i>TONSL</i> using RNAi revealed that it is required in the survival of CSCs in cancer cells, while BCCs could frequently survive without <i>TONSL</i>. <i>TONSL</i> dependency occurs through accumulated DNA damage-induced senescence and apoptosis in <i>TONSL</i>-suppressed CSCs. The expression of several other major mediators of HRR was also associated with worse prognosis, whereas the expression of error-prone nonhomologous end joining molecules was associated with better survival in lung adenocarcinoma. Collectively, these results suggest that TONSL-mediated HRR at the replication fork is critical for CSC survival; targeting TONSL may lead to the effective eradication of CSCs. |
| first_indexed | 2024-03-11T03:05:39Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:05:39Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-633a774111b546db93cf764c0206c2b92023-11-18T08:00:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411953010.3390/ijms24119530Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem CellsHani Lee0Sojung Ha1SeokGyeong Choi2Soomin Do3Sukjoon Yoon4Yong Kee Kim5Woo-Young Kim6College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of KoreaDepartment of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Republic of KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of KoreaWe investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cancer stem cell (CSC)-enriched cultures and bulk/general mixed cell cultures (BCCs) with RNAi were employed to determine the effect of <i>TONSL</i> loss in cancer cell lines from the ovary, breast, stomach, lung, colon and brain. Limited dilution assays and ALDH assays were used to quantify the loss of CSCs. Western blotting and cell-based homologous recombination assays were used to identify DNA damage derived from TONSL loss. <i>TONSL</i> was expressed at higher levels in cancer tissues than in normal tissues, and higher expression was an unfavorable prognostic marker for lung, stomach, breast and ovarian cancers. Higher expression of <i>TONSL</i> is partly associated with the coamplification of <i>TONSL</i> and <i>MYC</i>, suggesting its oncogenic role. The suppression of <i>TONSL</i> using RNAi revealed that it is required in the survival of CSCs in cancer cells, while BCCs could frequently survive without <i>TONSL</i>. <i>TONSL</i> dependency occurs through accumulated DNA damage-induced senescence and apoptosis in <i>TONSL</i>-suppressed CSCs. The expression of several other major mediators of HRR was also associated with worse prognosis, whereas the expression of error-prone nonhomologous end joining molecules was associated with better survival in lung adenocarcinoma. Collectively, these results suggest that TONSL-mediated HRR at the replication fork is critical for CSC survival; targeting TONSL may lead to the effective eradication of CSCs.https://www.mdpi.com/1422-0067/24/11/9530TONSLCSCMYCdouble-strand DNA damage repairhomologous recombination repairs |
| spellingShingle | Hani Lee Sojung Ha SeokGyeong Choi Soomin Do Sukjoon Yoon Yong Kee Kim Woo-Young Kim Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells International Journal of Molecular Sciences TONSL CSC MYC double-strand DNA damage repair homologous recombination repairs |
| title | Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells |
| title_full | Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells |
| title_fullStr | Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells |
| title_full_unstemmed | Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells |
| title_short | Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells |
| title_sort | oncogenic impact of tonsl a homologous recombination repair protein at the replication fork in cancer stem cells |
| topic | TONSL CSC MYC double-strand DNA damage repair homologous recombination repairs |
| url | https://www.mdpi.com/1422-0067/24/11/9530 |
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