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Cell Rep. 2015 Apr 14;11(2):210-9. doi: 10.1016/j.celrep.2015.03.019. Epub 2015 Apr 2.

E4F1 is a master regulator of CHK1-mediated functions.

Author information

1
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
2
Signaling and Cell Growth Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
3
Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
4
Genome Stability Laboratory, CHU de Quebec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.
5
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.
6
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.
7
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.

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.

PMID:
25843717
DOI:
10.1016/j.celrep.2015.03.019
[Indexed for MEDLINE]
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