title: Tumour suppressor ING1b maintains genomic stability upon replication stress.
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.
authors.affiliation: Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, ON, Canada V6H 3Z6.
authors.forename: Ronald P C
authors.initials: RP
authors.lastname: Wong
authors.forename: Hanyang
authors.initials: H
authors.lastname: Lin
authors.forename: Shahram
authors.initials: S
authors.lastname: Khosravi
authors.forename: Brad
authors.initials: B
authors.lastname: Piche
authors.forename: Seyed Mehdi
authors.initials: SM
authors.lastname: Jafarnejad
authors.forename: David W C
authors.initials: DW
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Li
mesh_terms: D000107:Acetylation; D002460:Cell Line; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016196:S Phase; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; C485954:RAD18 protein, human; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases