HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability.
CLASPIN is an essential mediator in the DNA replication checkpoint, responsible for ATR (ataxia telangiectasia and Rad3-related protein)-dependent activation of CHK1 (checkpoint kinase 1). Here we found a dynamic signaling pathway that regulates CLASPIN turn over. Under unperturbed conditions, the E3 ubiquitin ligase HERC2 regulates the stability of the deubiquitinating ... enzyme USP20 by promoting ubiquitination-mediated proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 results in the disassociation of HERC2 from USP20. USP20 in turn deubiquitinates K48-linked-polyubiquitinated CLASPIN, stabilizing CLASPIN and ultimately promoting CHK1 phosphorylation and CHK1-directed checkpoint activation. Inhibition of USP20 expression promotes chromosome instability and xenograft tumor growth. Taken together, our findings demonstrated a novel function of HERC2/USP20 in coordinating CHK1 activation by modulating CLASPIN stability, which ultimately promotes genome stability and suppresses tumor growth.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, DNA Replication, Enzyme Activation, Female, Guanine Nucleotide Exchange Factors, HEK293 Cells, Humans, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Phosphorylation, Protein Kinases, Protein Stability, Stress, Physiological, Ubiquitin Thiolesterase, Ultraviolet Rays
Adaptor Proteins, Signal Transducing, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, DNA Replication, Enzyme Activation, Female, Guanine Nucleotide Exchange Factors, HEK293 Cells, Humans, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Phosphorylation, Protein Kinases, Protein Stability, Stress, Physiological, Ubiquitin Thiolesterase, Ultraviolet Rays
Nucleic Acids Res.
Date: Dec. 01, 2014
PubMed ID: 25326330
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