title: E4F1 is a master regulator of CHK1-mediated functions.
abstract: 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.
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Grote
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Céline
authors.initials: C
authors.lastname: Moison
authors.affiliation: Signaling and Cell Growth Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Duhamel
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Jalila
authors.initials: J
authors.lastname: Chagraoui
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Girard
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Mayotte
authors.affiliation: Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Coulombe
authors.affiliation: Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, QC G1V 0A6, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.affiliation: Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
authors.affiliation: Signaling and Cell Growth Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Pharmacology, University of Montreal, Montreal, QC H3C 3J7, Canada. Electronic address: sylvain.meloche@umontreal.ca.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.affiliation: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada. Electronic address: guy.sauvageau@umontreal.ca.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D042822:Genomic Instability; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
chemical_list: C489421:Bmi1 protein, mouse; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C084953:E4f1 protein, mouse; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse