Sumoylation participates in the regulation of YB-1-mediated mismatch repair deficiency and alkylator tolerance
AJCR Copyright © 2022..
Numerous reports indicate that enhanced expression of Y-box binding protein-1 (YB-1) in tumor cells is strongly associated with tumorigenesis, aggressiveness, drug resistance, as well as poor prognosis in several types of cancers, and YB-1 is considered to be an oncogene. The molecular mechanism contributing to the regulation of the biological activities of YB-1 remains obscure. Sumoylation, a post-translational modification involving the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to a target protein, plays key roles in the modulation of protein functions. In this study, our results revealed that YB-1 is sumoylated and that Lys26 is a critical residue for YB-1 sumoylation. Moreover, YB-1 was found to directly interact with SUMO proteins, and disruption of the SUMO-interacting motif (SIM) of YB-1 not only interfered with this interaction but also diminished YB-1 sumoylation. The subcellular localization, protein stability, and transcriptional regulatory activity of YB-1 were not significantly affected by sumoylation. However, decreased sumoylation disrupted the interaction between YB-1 and PCNA as well as YB-1-mediated inhibition of the MutSα/PCNA interaction and MutSα mismatch binding activity, indicating a functional role of YB-1 sumoylation in inducing DNA mismatch repair (MMR) deficiency and spontaneous mutations. The MMR machinery also recognizes alkylator-modified DNA adducts to signal for cell death. We further demonstrated that YB-1 sumoylation is crucial for the inhibition of SN1-type alkylator MNNG-induced cytotoxicity, G2/M-phase arrest, apoptosis, and the MMR-dependent DNA damage response. Collectively, these results provide molecular explanations for the impact of YB-1 sumoylation on MMR deficiency and alkylator tolerance, which may provide insight for designing therapeutic strategies for malignancies and alkylator-resistant cancers associated with YB-1 overexpression.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
American journal of cancer research - 12(2022), 12 vom: 06., Seite 5462-5483 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mai, Ru-Tsun [VerfasserIn] |
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| Themen: |
Alkylator tolerance |
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| Anmerkungen: |
Date Revised 12.01.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| Förderinstitution / Projekttitel: |
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NLM351392955 |
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| 520 | |a AJCR Copyright © 2022. | ||
| 520 | |a Numerous reports indicate that enhanced expression of Y-box binding protein-1 (YB-1) in tumor cells is strongly associated with tumorigenesis, aggressiveness, drug resistance, as well as poor prognosis in several types of cancers, and YB-1 is considered to be an oncogene. The molecular mechanism contributing to the regulation of the biological activities of YB-1 remains obscure. Sumoylation, a post-translational modification involving the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to a target protein, plays key roles in the modulation of protein functions. In this study, our results revealed that YB-1 is sumoylated and that Lys26 is a critical residue for YB-1 sumoylation. Moreover, YB-1 was found to directly interact with SUMO proteins, and disruption of the SUMO-interacting motif (SIM) of YB-1 not only interfered with this interaction but also diminished YB-1 sumoylation. The subcellular localization, protein stability, and transcriptional regulatory activity of YB-1 were not significantly affected by sumoylation. However, decreased sumoylation disrupted the interaction between YB-1 and PCNA as well as YB-1-mediated inhibition of the MutSα/PCNA interaction and MutSα mismatch binding activity, indicating a functional role of YB-1 sumoylation in inducing DNA mismatch repair (MMR) deficiency and spontaneous mutations. The MMR machinery also recognizes alkylator-modified DNA adducts to signal for cell death. We further demonstrated that YB-1 sumoylation is crucial for the inhibition of SN1-type alkylator MNNG-induced cytotoxicity, G2/M-phase arrest, apoptosis, and the MMR-dependent DNA damage response. Collectively, these results provide molecular explanations for the impact of YB-1 sumoylation on MMR deficiency and alkylator tolerance, which may provide insight for designing therapeutic strategies for malignancies and alkylator-resistant cancers associated with YB-1 overexpression | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DNA damage response | |
| 650 | 4 | |a DNA mismatch repair | |
| 650 | 4 | |a SUMO-interacting motif | |
| 650 | 4 | |a YB-1 | |
| 650 | 4 | |a alkylator tolerance | |
| 650 | 4 | |a sumoylation | |
| 700 | 1 | |a Chao, Chi-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Yao-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Kao, Yu-Ching |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Hsu, Hsiang-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Yi-Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen-Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Lai, Bo-Ying |e verfasserin |4 aut | |
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