Genome-wide screening for deubiquitinase subfamily identifies ubiquitin-specific protease 49 as a novel regulator of odontogenesis

Kamini Kaushal, Eun Jung Kim, Apoorvi Tyagi, Janardhan Keshav Karapurkar, Saba Haq, Han Sung Jung, Kye Seong Kim, Suresh Ramakrishna

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Proteins expressed by the paired box gene 9 (PAX9) and Msh Homeobox 1 (MSX1) are intimately involved in tooth development (odontogenesis). The regulation of PAX9 and MSX1 protein turnover by deubiquitinating enzymes (DUBs) plausibly maintain the required levels of PAX9 and MSX1 during odontogenesis. Herein, we used a loss-of-function CRISPR-Cas9-mediated DUB KO library kit to screen for DUBs that regulate PAX9 and MSX1 protein levels. We identify and demonstrate that USP49 interacts with and deubiquitinates PAX9 and MSX1, thereby extending their protein half-lives. On the other hand, the loss of USP49 reduces the levels of PAX9 and MSX1 proteins, which causes transient retardation of odontogenic differentiation in human dental pulp stem cells and delays the differentiation of human pluripotent stem cells into the neural crest cell lineage. USP49 depletion produced several morphological defects during tooth development, such as reduced dentin growth with shrunken enamel space, and abnormal enamel formation including irregular mineralization. In sum, our results suggest that deubiquitination of PAX9 and MSX1 by USP49 stabilizes their protein levels to facilitate successful odontogenesis.

Original languageEnglish
Pages (from-to)1689-1704
Number of pages16
JournalCell Death and Differentiation
Issue number9
Publication statusPublished - 2022 Sept

Bibliographical note

Funding Information:
The authors acknowledge Dr. Arun Pandian Chandrasekaran for his technical support. This research was supported by the Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government (MSIP and MOHW) (2016R1A5A2008630, 2017M3A9E4048172, 2017M3A9B3061830, 2017M3A9C6061361, 2021M3A9H3015389 and 2022R1A2B5B03001627).

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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