YB-1 disrupts mismatch repair complex formation, interferes with MutSα recruitment on mismatch and inhibits mismatch repair through interacting with PCNA

Chang, Y-WY-WChangMai, R-TR-TMaiWOEI-HORNG FANGLin, C-CC-CLinChiu, C-CC-CChiuWu Lee, Y-HY-HWu Lee2022-11-012022-11-012014-10-230950-9232https://scholars.lib.ntu.edu.tw/handle/123456789/624336Y-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.enYB-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[SDGs]SDG2YB-1 disrupts mismatch repair complex formation, interferes with MutSα recruitment on mismatch and inhibits mismatch repair through interacting with PCNAjournal article10.1038/onc.2013.450241417882-s2.0-85027945611WOS:000343768400002https://scholars.lib.ntu.edu.tw/handle/123456789/380785