E4F1 Is a Master Regulator of CHK1-Mediated Functions
David Grote,
Céline Moison,
Stéphanie Duhamel,
Jalila Chagraoui,
Simon Girard,
Jay Yang,
Nadine Mayotte,
Yan Coulombe,
Jean-Yves Masson,
Grant W. Brown,
Sylvain Meloche,
Guy Sauvageau
Affiliations
David Grote
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Céline Moison
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Stéphanie Duhamel
Signaling and Cell Growth Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Jalila Chagraoui
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Simon Girard
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Jay Yang
Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Nadine Mayotte
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Yan Coulombe
Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada
Jean-Yves Masson
Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada
Grant W. Brown
Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Sylvain Meloche
Signaling and Cell Growth Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
Guy Sauvageau
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
It has been previously shown that the polycomb protein BMI1 and E4F1 interact physically and genetically in the hematopoietic system. Here, we report that E4f1 is essential for hematopoietic cell function and survival. E4f1 deletion induces acute bone marrow failure characterized by apoptosis of progenitors while stem cells are preserved. E4f1-deficient cells accumulate DNA damage and show defects in progression through S phase and mitosis, revealing a role for E4F1 in cell-cycle progression and genome integrity. Importantly, we showed that E4F1 interacts with and protects the checkpoint kinase 1 (CHK1) protein from degradation. Finally, defects observed in E4f1-deficient cells were fully reversed by ectopic expression of Chek1. Altogether, our results classify E4F1 as a master regulator of CHK1 activity that ensures high fidelity of DNA replication, thus safeguarding genome stability.
