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Deciphering the role of post-translational modifications in fanconi anemia proteins and their influence on tumorigenesis

Abstract

Fanconi anemia (FA) is an autosomal or X-linked human disease, characterized by bone marrow failure, cancer susceptibility and various developmental abnormalities. So far, at least 22 FA genes (FANCA-W) have been identified. Germline inactivation of any one of these FA genes causes FA symptoms. Proteins encoded by FA genes are involved in the Fanconi anemia pathway, which is known for its roles in DNA inter-strand crosslinks (ICLs) repair. Besides, its roles in genome maintenance upon replication stress has also been reported. Post-translational modifications (PTMs) of FA proteins, particularly phosphorylation and ubiquitination, emerge as critical determinants in the activation of the FA pathway during ICL repair or replication stress response. Consequent inactivation of the FA pathway engenders heightened chromosomal instability, thereby constituting a genetic susceptibility conducive to cancer predisposition and the exacerbation of tumorigenesis. In this review, we have combined recent structural analysis of FA proteins and summarized knowledge on the functions of different PTMs in regulating FA pathways, and discuss potential contributions stemming from mutations at PTMs to the genesis and progression of tumorigenesis.

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Fig. 1: The Fanconi anemia pathway in ICL repair.
Fig. 2: Schematic of the human FA core complex.
Fig. 3: Proposed activation and inactivation model of the FANCD2-I complex by phosphorylation and monoubiquitination.
Fig. 4: The impact of PTMs mutations on tumors.

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Acknowledgements

This work was supported by Foundation of Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province (Grant No. FYYFEJB2024005 to X.X.) and Hubei Provincial Natural Science Foundation of China (Grant No. 2024AFB473 to X.X.).

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XX and MR drafted the manuscript; MR completed the table and XX completed the figures; All authors have read and approved the final manuscript.

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Correspondence to Xinlin Xu.

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Ma, R., Xu, X. Deciphering the role of post-translational modifications in fanconi anemia proteins and their influence on tumorigenesis. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00797-1

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