4.6 Article

Sumoylation participates in the regulation of YB-1-mediated mismatch repair deficiency and alkylator tolerance

Journal

AMERICAN JOURNAL OF CANCER RESEARCH
Volume 12, Issue 12, Pages 5462-+

Publisher

E-CENTURY PUBLISHING CORP

Keywords

YB-1; sumoylation; SUMO-interacting motif; DNA mismatch repair; DNA damage response; alkylator tolerance

Categories

Funding

  1. Taiwan Ministry of Science and Technology [MOST 107-2320-B-009-006-MY2, MOST 109-2320-B-009-002, MOST 107-2628-B-009-002, MOST 108-2628-B-009-002, MOST 109-2628-B-009-004]
  2. Ministry of Education (MOE) in Taiwan
  3. Higher Education Sprout Project of National Yang Ming Chiao Tung University
  4. Taiwan Ministry of Science and Technology [MOST 111-2321-B-A49-010]

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Numerous reports indicate that enhanced expression of Y-box binding protein-1 (YB-1) is strongly associated with tumorigenesis, aggressiveness, drug resistance, as well as poor prognosis in several types of cancers. This study reveals the sumoylation of YB-1 and its crucial role in DNA mismatch repair deficiency and alkylator tolerance.
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 Lys(26) 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 MutSa/PCNA interaction and MutSa 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 explana-tions 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 overexpres-sion.

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