Dido3 PHD Modulates Cell Differentiation and Division
Jovylyn Gatchalian,
Agnes Fütterer,
Scott B. Rothbart,
Qiong Tong,
Hector Rincon-Arano,
Ainhoa Sánchez de Diego,
Mark Groudine,
Brian D. Strahl,
Carlos Martínez-A,
Karel H.M. van Wely,
Tatiana G. Kutateladze
Affiliations
Jovylyn Gatchalian
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Agnes Fütterer
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain
Scott B. Rothbart
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Qiong Tong
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Hector Rincon-Arano
Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Ainhoa Sánchez de Diego
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain
Mark Groudine
Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Brian D. Strahl
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Carlos Martínez-A
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain
Karel H.M. van Wely
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain
Tatiana G. Kutateladze
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Death Inducer Obliterator 3 (Dido3) is implicated in the maintenance of stem cell genomic stability and tumorigenesis. Here, we show that Dido3 regulates the expression of stemness genes in embryonic stem cells through its plant homeodomain (PHD) finger. Binding of Dido3 PHD to histone H3K4me3 is disrupted by threonine phosphorylation that triggers Dido3 translocation from chromatin to the mitotic spindle. The crystal structure of Dido3 PHD in complex with H3K4me3 reveals an atypical aromatic-cage-like binding site that contains a histidine residue. Biochemical, structural, and mutational analyses of the binding mechanism identified the determinants of specificity and affinity and explained the inability of homologous PHF3 to bind H3K4me3. Together, our findings reveal a link between the transcriptional control in embryonic development and regulation of cell division.
