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Tumour suppressor ING1b maintains genomic stability upon replication stress

By Ronald P. C. Wong, Hanyang Lin, Shahram Khosravi, Brad Piche, Seyed Mehdi Jafarnejad, David W. C. Chen and Gang Li

Abstract

The lesion bypass pathway, which is regulated by monoubiquitination of proliferating cell nuclear antigen (PCNA), is essential for resolving replication stalling due to DNA lesions. This process is important for preventing genomic instability and cancer development. Previously, it was shown that cells deficient in tumour suppressor p33ING1 (ING1b) are hypersensitive to DNA damaging agents via unknown mechanism. In this study, we demonstrated a novel tumour suppressive function of ING1b in preserving genomic stability upon replication stress through regulating PCNA monoubiquitination. We found that ING1b knockdown cells are more sensitive to UV due to defects in recovering from UV-induced replication blockage, leading to enhanced genomic instability. We revealed that ING1b is required for the E3 ligase Rad18-mediated PCNA monoubiquitination in lesion bypass. Interestingly, ING1b-mediated PCNA monoubiquitination is associated with the regulation of histone H4 acetylation. Results indicate that chromatin remodelling contributes to the stabilization of stalled replication fork and to the regulation of PCNA monoubiquitination during lesion bypass

Topics: Genome Integrity, Repair and Replication
Publisher: Oxford University Press
OAI identifier: oai:pubmedcentral.nih.gov:3089469
Provided by: PubMed Central

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