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  Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor

Huang, Y.-H., Chen, C.-W., Sundaramurthy, V., Słabicki, M., Hao, D., Watson, C. J., et al. (2021). Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor. Cancer Discovery, CD-21-0560. doi:10.1158/2159-8290.CD-21-0560.

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 Creators:
Huang, Yung-Hsin , Author
Chen, Chun-Wei , Author
Sundaramurthy, Venkatasubramaniam, Author
Słabicki, Mikołaj , Author
Hao, Dapeng , Author
Watson, Caroline J. , Author
Tovy, Ayala , Author
Reyes, Jaime M. , Author
Dakhova, Olga, Author
Crovetti, Brielle R. , Author
Galonska, Christina1, Author           
Lee, Minjung , Author
Brunetti, Lorenzo , Author
Zhou, Yubin , Author
Tatton-Brown, Katrina , Author
Huang, Yun, Author
Cheng, Xiaodong , Author
Meissner, Alexander1, Author           
Valk, Peter J. M. , Author
Van Maldergem, Lionel , Author
Sanders, Mathijs A. , AuthorBlundell, Jamie R., AuthorLi, Wei, AuthorEbert, Benjamin L. , AuthorGoodell, Margaret A. , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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Free keywords: Clonal hematopoiesis; hematological malignancies; DNMT3A variants; E3 ubiquitin ligases; protein instability
 Abstract: Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease.

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Language(s): eng - English
 Dates: 2021-08-192021-08-24
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1158/2159-8290.CD-21-0560
 Degree: -

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Title: Cancer Discovery
Source Genre: Journal
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Publ. Info: Philadelphia, Pennsylvania : American Association for Cancer Research
Pages: - Volume / Issue: - Sequence Number: CD-21-0560 Start / End Page: - Identifier: ISSN: 2159-8274 (print) 2159-8290 (online)