Loss of protein phosphatase 4 inhibitory protein leads to genomic instability and heightens vulnerability to replication stress

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 6; p. 130797
• Main Authors: Park, Jaehong, Lee, Dong-Hyun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2025
• Subjects: Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Repair; DNA Replication; Genomic Instability; Genomic stability; Humans; p21; Protein phosphatase 4 inhibitory protein; Replication stress; Tumor Suppressor p53-Binding Protein 1 - genetics; Tumor Suppressor p53-Binding Protein 1 - metabolism; Protein phosphatase 4 inhibitory protein; Genomic stability; Replication stress; p21
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2025.130797

Protein phosphatase 4 inhibitory protein (PP4IP) has recently emerged as a key player in cellular processes, particularly in DNA double-strand break repair and telomere maintenance, although research on its functions remains limited. To further investigate the cellular pathways involving PP4IP, we conducted transcriptomic analysis via RNA sequencing in PP4IP-knockout cells and observed an upregulation of p21 expression. This upregulation was linked to an increased population of p21-positive G1-phase cells in the absence of PP4IP. Prior studies have suggested that unresolved under-replicated DNA in mother cells, transmitted to daughter cells, can trigger a quiescent G1 phase characterized by p21 expression and the formation of p53-binding protein 1 (53BP1) nuclear bodies. Consistent with this, we found a higher proportion of 53BP1 nuclear bodies-positive G1 cells in PP4IP-knockout cells compared to controls. Additionally, PP4IP-deficient cells displayed an increased occurrence of anaphase bridges—indicative of incomplete DNA replication—without a corresponding increase in lagging chromosomes. Furthermore, PP4IP-knockout cells exhibited a heightened susceptibility to replication stress, as evidenced by an elevated frequency of replication stress-induced chromatid breaks and increased sensitivity to such stress. Collectively, these results suggest that PP4IP plays a critical role in safeguarding cells from replication stress and ensuring genomic stability. [Display omitted] •Transcriptome analysis was performed to find out PP4IP-related pathways.•PP4IP deficiency increases p21-positive G1 population.•Formation of 53BP1 nuclear bodies in G1 cells increases in PP4IP-knockout cells.•Genomic stability is impaired by PP4IP deficiency.