RFWD3: A pivotal E3 ubiquitin ligase in DNA damage response, non-neoplastic disorders and multi-system tumorigenesis.

Authors

Yue Ding, Mingyue Zhu, Jiaping Shu, Guxin Zhou, Rong Jin, Min Chen, Ru Zhang, Fangyuan Chang

Published in

Science progress. Volume 109. Issue 3. Pages 368504261480981. Epub Aug 19, 2026.

Abstract

RFWD3 is a multifunctional RING-type E3 ubiquitin ligase and a central hub in the DNA damage response (DDR) network. It regulates replication fork stability, homologous recombination repair, and cell cycle checkpoints through K63-linked ubiquitination of critical DDR effectors, thereby safeguarding genomic integrity. Germline RFWD3 dysfunction disrupts genomic homeostasis, leading to hereditary non-neoplastic disorders, including Fanconi anemia and premature ovarian insufficiency, while somatic aberrations drive tumorigenesis across multiple organ systems. This narrative review summarizes the molecular mechanisms underlying RFWD3 function in the DDR network, then examines its roles in non-neoplastic disorders and tumorigenesis, and finally integrates recent advances from molecular genetics to translational medicine. Additionally, this review highlights the context-dependent oncogenic and tumor-suppressive functions of RFWD3 in different disease settings and provides a theoretical framework for the precision diagnosis, prognostic stratification, and targeted intervention of RFWD3-associated disorders.

PMID:
42615306
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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