Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8), an ubiquitin-like protein, is an essential regulator for the DNA damage response. Numerous studies have shown that neddylation dysfunction causes several human diseases, such as cancer. Hence, clarifying the regulatory mechanism for neddylation could provide insight into the mechanism of genome stability underlying the DNA damage response (DDR) and carcinogenesis. Here, we demonstrate that dual-specificity tyrosine-regulated kinase 2 (DYRK2) is a novel regulator of neddylation and maintains genome stability. Deletion of DYRK2 leads to persistent DNA double-stand breaks (DSBs) and subsequent genome instability. Mechanistically, DYRK2 promotes neddylation through forming a complex with NAE1, which is a component of NEDD8-activating enzyme E1, and maintaining its protein level by suppressing polyubiquitination. The present study is the first to demonstrate that DYRK2 controls neddylation and is necessary for maintaining genome stability.
DYRK2 maintains genome stability via neddylation of cullins in response to DNA damage
These authors contributed equally to this work.
- Award Group:
- Funder(s): Japan Society for the Promotion of Science
- Award Id(s): 17H03584
- Funder(s):
- Award Group:
- Funder(s): Takeda Science Foundation
- Award Id(s): none
- Funder(s):
- Award Group:
- Funder(s): Uehara Memorial Foundation
- Award Id(s): none
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
Akira Kawamura, Saishu Yoshida, Katsuhiko Aoki, Yuya Shimoyama, Kohji Yamada, Kiyotsugu Yoshida; DYRK2 maintains genome stability via neddylation of cullins in response to DNA damage. J Cell Sci 2022; jcs.259514. doi: https://doi.org/10.1242/jcs.259514
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