ZFP161 regulates replication fork stability and maintenance of genomic stability by recruiting the ATR/ATRIP complex

Abstract

DNA replication stress-mediated activation of the ATR kinase pathway is important for maintaining genomic stability. In this study, we identified a zinc finger protein, ZFP161 that functions as a replication stress response factor in ATR activation. Mechanistically, ZFP161 acts as a scaffolding protein to facilitate the interaction between RPA and ATR/ATRIP. ZFP161 binds to RPA and ATR/ATRIP through distinct regions and stabilizes the RPA–ATR–ATRIP complex at stalled replication forks. This function of ZFP161 is important to the ATR signaling cascade and genome stability maintenance. In addition, ZFP161 knockout mice showed a defect in ATR activation and genomic instability. Furthermore, low expression of ZFP161 is associated with higher cancer risk and chromosomal instability. Overall, these findings suggest that ZFP161 coordinates ATR/Chk1 pathway activation and helps maintain genomic stability.

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

“…Therefore, the purpose of this study was to show that the efficacy of PARP inhibition can be increased by targeting critical cell cycle checkpoints, which may cause a significant reduction in the survival of EOC lines. Because the ATR/CHK1 pathway stabilizes replication forks and prevents DSBs [ 36 ], inhibition of ATR/CHK1 is expected to increase dependence on HR to complete replication. The combination of olaparib with anticancer agents that disrupt HR repair, namely, ATRi or CHK1i, represents a novel strategy to effectively sensitize ovarian cancer cells to olaparib.…”

Epigenetic clock and methylation studies in cats

“…As mentioned above TFAP2 is a transcription factor whose target genes are involved in the cellular differentiation and organ development. ZFP161 protein binds to GC-rich DNA regions, regulates DNA replication fork stability and maintains genomic stability 38 . It is interesting that another genomic stabilizing protein, the retinoblastoma protein (RB) exerts it effect through binding the E2F transcription factor 39,40 , whose binding sites become increasingly methylated with age in these two species.…”

DNA methylation predicts age and provides insight into exceptional longevity of bats

“…5e ). Several of those transcription factors, including Cut-like homeobox 1 (CUX1), AT-rich interaction domain 3A (ARID3), and E2f transcription factor 1 (E2F) are involved in cell cycle regulation 35 – 37 , while others, such as Zinc finger protein 161 (ZFP161), are involved in genome stability 38 . In contrast, hypomethylating age sites only overlap three TF clusters, one of which, IRF7, is a master regulator of the interferon-dependent innate immune response in bats 39 .…”