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KMID : 1161520150190040236
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Animal Cells and Systems
2015 Volume.19 No. 4 p.236 ~ p.244
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Protein DHX38 is a novel inhibitor of protein phosphatase 4
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Han Sue-Ji
Park Jae-Hong
Lee Dong-Hyun
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Abstract
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DHX38 is a DEAH-box RNA helicase involved in RNA splicing. Recently, there was a report that DHX38 interacts with protein phosphatase 4 (PP4) as a subunit of PP4 complex. However, the role of DHX38 in connection with the function of PP4 has not been elucidated. Here, we demonstrated a functional role of DHX38 as an inhibitor of PP4 complex. We observed that DHX38 interacts with PP4 subunits (PP4R2, PP4R3α, PP4R3β, and PP4C), except PP4R1, and there is no significant change in the interaction between DHX38 and PP4 after DNA damage, suggesting that interaction is damage-independent. Furthermore, DHX38 has no detectable association with other Seine/Threonine phosphatases, implying that DHX38 interacts with PP4 in a phosphatase-specific manner. Interestingly, we observed that the amount of PP4R2 is substantially elevated when DHX38 is absent, but there is no effect on other subunits. Consequently, the stabilization of PP4R2 enhances PP4C/PP4R2-mediated dephosphorylation of target proteins, RPA2, and KAP1. In contrast, overexpressing DHX38 inhibits dephosphorylational activity of PP4, which is compatible with PP4C or PP4R2 depletion. Consistent with previous observations that PP4R2 is essential for DNA replication and double-strand DNA breaks (DSBs) repairs, the inhibition of PP4R2 by DHX38 expression significantly impairs these processes and the depletion of DHX38 expectedly promotes them. Defects in the efficiency of DNA replication and DSB repairs would be expected to be biologically relevant and indeed, cells expressing DHX38 have lower viability than control cells. Together, our results suggest that DHX38 functions as an endogenous inhibitor of PP4 by disrupting PP4C/PP4R2-mediated functions.
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KEYWORD
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DEAH (Asp-Glu-Ala-His) box polypeptide 38, protein phosphatase 4, DNA damage response, dephosphorylation
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