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The stability of epigenetic factor ASXL1 is regulated through ubiquitination and USP7-mediated deubiquitination

Leukemia volume 29, pages 2257–2260 (2015)Cite this article

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Additional sex combs like transcriptional regulator 1 (ASXL1) is indispensable for normal development and myeloid differentiation.1, 2, 3 Mutation of ASXL1 is one of the most common mutations among various myeloid malignancies, especially in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia, and is an independent poor prognostic factor among patients with MDS.4 We previously demonstrated that the expression of C-terminal-truncated ASXL1 inhibited myeloid differentiation and induced an MDS-like disease in mice through the dominant-negative repression of polycomb repressive complex 2 (PRC2) function.3 Asxl1 KO mice developed similar diseases,1 suggesting that regulation of ASXL1 expression or turnover of ASXL1 proteins is closely associated with myeloid malignancies. However, how the expression levels of ASXL1 proteins are regulated remains to be elucidated. Furthermore, endogenous ASXL1 proteins are usually difficult to detect, suggesting the fragility of ASXL1. In this study, we demonstrate that ASXL1 is subject to K351 ubiquitination and subsequent degradation, and that interaction with the deubiquitinating enzyme, ubiquitin-specific peptidase 7 (USP7), stabilizes ASXL1.

As far as we know, this is the first report on the ubiquitination-mediated regulation of ASXL1. We have shown that the ubiquitination of K351 is critical for ASXL1 degradation and that USP7, a well-studied DUB, can interact with and stabilize ASXL1. Given that ASXL1 is important for axial patterning during normal development and myeloid differentiation,1, 3, 6 the mechanisms by which its expression is tightly and dynamically regulated appear critical for normal development and differentiation. On the other hand, deregulation of ASXL1 could result in the development of MDS because mutations of ASXL1 and polycomb repressive complex 2 (PRC2) components are common among MDS patients.7 In addition, recent bioinformatics analysis suggested that the N-terminal domain of ASXL1 (amino acids 10–100) represents a unique DNA binding motif, and that ASXL1 acts as a scaffold for PRC2 to regulate gene expression.8 Although most ASXL1 mutations are found in the 5′-end of the last exon, leading to escaping nonsense-mediated mRNA decay, and express the C-terminal truncating mutant forms of ASXL1, missense mutations, but not single-nucleotide polymorphisms, were also detected in a small proportion of MDS patients.9 Considering that ASXL1 is predicted to contain some PEST sequences which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) (data not shown), whether some missense mutations decrease protein stability remains to be elucidated, although mutations at K351 have not yet been reported.

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Authors and Affiliations

  1. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo,, Japan

    D Inoue, K Nishimura & T Kitamura

  2. Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    H Kozuka-Hata & M Oyama

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  1. D Inoue
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Correspondence to T Kitamura.

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Inoue, D., Nishimura, K., Kozuka-Hata, H. et al. The stability of epigenetic factor ASXL1 is regulated through ubiquitination and USP7-mediated deubiquitination. Leukemia 29, 2257–2260 (2015). https://doi.org/10.1038/leu.2015.90

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