DSIF Restricts NF-kappa B Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes

作者：Diamant Gil; Amir Zilberstein Liat; Yamaguchi Yuki; Handa Hiroshi; Dikstein Rivka^*

来源：Cell Reports, 2012, 2(4): 722-731.

DOI：10.1016/j.celrep.2012.08.041

NF-kappa B is central for immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer through poorly defined mechanisms. IkB alpha and A20 are NF-kappa B target genes and negative feedback regulators. Upon their activation by NF-kappa B, DSIF is recruited, P-TEFb is released, and their elongating polymerase II (Pol II) C-terminal domain (CTD) remains hypophosphorylated. We show that upon DSIF knockdown, mRNA levels of a subset of NF-kappa B targets are not diminished; yet much less IkB alpha and A20 protein are synthesized, and NF-kappa B activation is abnormally prolonged. Further analysis of IkB alpha and A20 mRNA revealed that a significant portion is uncapped, unspliced, and retained in the nucleus. Interestingly, the Spt5 C-terminal repeat (CTR) domain involved in elongation stimulation through P-TEFb is dispensable for IkB alpha and A20 regulation. These findings assign a function for DSIF in cotranscriptional mRNA processing when elongating Pol II is hypophosphorylated and define DSIF as part of the negative feedback regulation of NF-kappa B.

• 出版日期2012-10