YB-1 disrupts mismatch repair complex formation, interferes with MutSα recruitment on mismatch and inhibits mismatch repair through interacting with PCNA
Journal
Oncogene
Journal Volume
33
Journal Issue
43
Pages
5065
Date Issued
2014-10-23
Author(s)
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.
Subjects
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
SDGs
Publisher
NATURE PUBLISHING GROUP
Type
journal article