Document Type
Article
Publication Date
2022
Digital Object Identifier (DOI)
https://doi.org/10.1101/mcs.a006212
Abstract
Chung–Jansen syndrome (CJS) is a rare, autosomal dominant disorder characterized by developmental delay, intellectual disability/cognitive impairment, behavioral challenges, obesity, and dysmorphic features. CJS is associated with heterozygous variants in PHIP (Pleckstrin-Homology Interacting Protein), a gene that encodes one of several substrate receptors for Cullin4-RING (CRL4) E3 ubiquitin ligase complex. Full-length PHIP, also called DCAF14, was recently identified to function as a replication stress response protein. Herein, we report the identification of two PHIP missense variants identified by exome sequencing in unrelated individuals with CJS. The variants p.D488V and p.E963G occur in different functional elements of DCAF14-WD40 repeat domain and pleckstrin homology-binding region (PBR), respectively. Using DNA fiber assays, we reveal that cells expressing either variant exhibit defective replication fork progression in conditions of replication stress. Furthermore, unlike wild-type DCAF14, both variants fail to accomplish DNA replication after exposure to genotoxic stress indicating a critical role of DCAF14 in protecting stalled replication forks. Thus, we have identified replication defects associated with CJS variants and predict replication-associated genome instability with CJS syndrome.
Rights Information
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Cold Spring Harbor Molecular Case Studies, v. 8, issue 5, art. a006212
Scholar Commons Citation
Tirado-Class, Neysha; Hathaway, Caitlin; Chung, Wendy K.; and Dungrawala, Huzefa, "PHIP Variants Associated with Chung–jansen Syndrome Disrupt Replication Fork Stability and Genome Integrity" (2022). Molecular Biosciences Faculty Publications. 99.
https://digitalcommons.usf.edu/bcm_facpub/99
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