HERP, a novel heterodimer partner of HES/E(spl) in notch signaling

HERP1 and -2 are members of a new basic helix-loop-helix (bHLH) protein fam ily closely related to HES/E(spl), the only previously known Notch effector . Like that of HES, HERP mRNA expression is directly up-regulated by Notch ligand binding without de novo protein synthesis. HES and HERP are individu ally expressed in certain cells, but they are also coexpressed within singl e cells after Notch stimulation. Here, we show that HERP has intrinsic tran scriptional repression activity. Transcriptional repression by HES/E(spl) e ntails the recruitment of the corepressor TLE/Groucho via a conserved WRPW motif, whereas unexpectedly the corresponding-but modified-tetrapeptide mot if in HERP confers marginal repression. Rather, HERP uses its bHLH domain t o recruit the mSin3 complex containing histone deacetylase HDAC1 and an add itional corepressor, N-CoR, to mediate repression. HES and HER-P homodimers bind similar DNA sequences, but with distinct sequence preferences, and th ey repress transcription from specific DNA binding sites. Importantly, HES and HERP associate with each other in solution and form a stable HES-HERP h eterodimer upon DNA binding. HES-HER-P heterodimers have both a greater DNA binding activity and a stronger repression activity than do the respective homodimers. Thus, Notch signaling relies on cooperation between HES and HE RP, two transcriptional repressors with distinctive repression mechanisms w hich, either as homo- or as heterodimers, regulate target gene expression.