Systematic Profiling of <i>DNMT3A</i> Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.

ABSTRACT: Clonal hematopoiesis is a prevalent age-related condition associated with a 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 are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found 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 acute myeloid leukemia development. We investigated the mechanisms un

SUBMITTER: Huang YH 

PROVIDER: S-EPMC8758508 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature