https://scholars.lib.ntu.edu.tw/handle/123456789/624336
Title: | YB-1 disrupts mismatch repair complex formation, interferes with MutSα recruitment on mismatch and inhibits mismatch repair through interacting with PCNA | Authors: | Chang, Y-W Mai, R-T WOEI-HORNG FANG Lin, C-C Chiu, C-C Wu Lee, Y-H |
Keywords: | YB-1; PCNA; PIP-box; mismatch repair; MutS alpha; genome instability; CELL NUCLEAR ANTIGEN; VIRUS CORE PROTEIN; BOX BINDING-PROTEIN; MICROSATELLITE INSTABILITY; ALKYLATING-AGENTS; MISPAIRED BASES; DNA-DAMAGE; GLIOBLASTOMA-MULTIFORME; GENE-EXPRESSION; REPLICATION | Issue Date: | 23-Oct-2014 | Publisher: | NATURE PUBLISHING GROUP | Journal Volume: | 33 | Journal Issue: | 43 | Start page/Pages: | 5065 | Source: | Oncogene | Abstract: | Y-box binding protein-1 (YB-1) is highly expressed in tumors and it participates in various cellular processes. Previous studies indicated that YB-1 binds to mispaired DNA and interacts with several mismatch repair (MMR)-related factors. However, its role in the MMR system remains undefined. Here, we found that YB-1 represses mutS homolog 6 (MSH6)-containing MMR complex formation and reduces MutSα mismatch binding activity by disrupting interactions among MMR-related factors. In an effort to elucidate how YB-1 exerts this inhibitory effect, we have identified two functional proliferating cell nuclear antigen (PCNA)-interacting protein (PIP)-boxes that mediate YB-1/PCNA interaction and locate within the C-terminal region of YB-1. This interaction is critical for the regulatory role of YB-1 in repressing MutSα mismatch binding activity, disrupting MutSα/PCNA/G/T heteroduplex ternary complex formation and inhibiting in vitro MMR activity. The differential regulation of 3' and 5' nick-directed MMR activity by YB-1 was also observed. Moreover, YB-1 overexpression is associated with the alteration of microsatellite pattern and the enhancement of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced and spontaneous mutations. Furthermore, upregulation of other PIP-box-containing proteins, such as myeloid cell leukemia-1 (Mcl-1) and inhibitor of growth protein 1b (ING1b), has no impact on MMR complex formation and mutation accumulation, thus revealing the significant effect of YB-1 on regulating the MMR system. In conclusion, our study suggests that YB-1 functions as a PCNA-interacting factor to exert its regulatory role on the MMR process and involves in the induction of genome instability, which may partially account for the oncogenic potential of YB-1. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/624336 | ISSN: | 0950-9232 | DOI: | 10.1038/onc.2013.450 |
Appears in Collections: | 醫學檢驗暨生物技術學系 |
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