Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 21, Pages 11624-11635Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1921115117
Keywords
activation-induced cytidine deaminase; heterogeneous nuclear ribonucleoprotein K; RNA-binding motifs; DNA breaks; IgH
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Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI [19H01027, 19K06485]
- JSPS KAKENHI [16H06279]
- China Scholarship Council
- Japanese Government (Ministry of Education, Culture, Sports, Science and Technology)
- Grants-in-Aid for Scientific Research [19H01027, 19K06485] Funding Source: KAKEN
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Activation-induced cytidine deaminase (AID) is the key enzyme for class switch recombination (CSR) and somatic hypermutation (SHM) to generate antibody memory. Previously, heterogeneous nuclear ribonucleoprotein K (hnRNP K) was shown to be required for AID-dependent DNA breaks. Here, we defined the function of major RNA-binding motifs of hnRNP K, GXXGs and RGGs in the K-homology (KH) and the K-protein-interaction (KI) domains, respectively. Mutation of GXXG, RGG, or both impaired CSR, SHM, and cMyc/IgH translocation equally, showing that these motifs were necessary for AID-dependent DNA breaks. AID-hnRNP K interaction is dependent on RNA; hence, mutation of these RNA-binding motifs abolished the interaction with AID, as expected. Some of the polypyrimidine sequence-carrying prototypical hnRNP K-binding RNAs, which participate in DNA breaks or repair bound to hnRNP K in a GXXG and RGG motif-dependent manner. Mutation of the GXXG and RGG motifs decreased nuclear retention of hnRNP K. Together with the previous finding that nuclear localization of AID is necessary for its function, lower nuclear retention of these mutants may worsen their functional deficiency, which is also caused by their decreased RNA-binding capacity. In summary, hnRNP K contributed to AID-dependent DNA breaks with all of its major RNA-binding motifs.
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