Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1 ؊/؊ mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1 ؊/؊ mice show only minor skeletal defects. However, Wwtr1 ؊/؊ animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CD). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1 ؊/؊ kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.bone ͉ cilia ͉ cysts ͉ glomerulus ͉ gene expression
Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and enzyme-independent motif recognition, PARP1 also plays important roles in regulating gene expression. Besides presenting current findings on how each process is individually controlled by PARP1, we shall discuss how transcription and DNA repair are so intricately linked that disturbance by PARP1 enzymatic inhibition, enzyme hyperactivation in diseases, and viral replication can favor one function while suppressing the other.
Significance
Killer cell immunoglobulin-like receptors (KIRs) function as key recognition elements in innate immunity. Structural information for inhibitory KIRs 2DL2, 2DL1, and 3DL1 in complex with their respective HLA ligands is available, but such data for activating KIRs are lacking. We report here the successful crystallization and solved structure of the activating KIR2DS2 in complex with HLA-A*11:01. The structure clearly explains the role of Tyr45, which has long puzzled KIR researchers because it differentiates KIR2DS2 from all inhibitory KIRs, and is now shown to bind Thr80 of HLA-A*11:01. Using KIR2DS2 tetramers to bind HLA on live cells, we also provide evidence that peptide sequence can affect KIR–HLA binding. Our data thus resolve a long-standing problem in KIR biology.
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