Open AccessInactivation of Chk2 and Mus81 Leads to Impaired Lymphocytes Development, Reduced Genomic Instability, and Suppression of Cancer
Author(s) -
Samah El Ghamrasni,
Ashwin Pamidi,
Marie Jo Halaby,
Miyuki Bohgaki,
Renato Cardoso,
Li Li,
Venkatesan Somasundaram,
Swaminathan Sethu,
Atsushi Hirao,
Tak W. Mak,
M. Prakash Hande,
Anne Hakem,
Razqallah Hakem
Publication year - 2011
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1001385
Subject(s) - biology , genome instability , dna damage , microbiology and biotechnology , effector , suppressor , mitosis , cell cycle checkpoint , mitotic catastrophe , programmed cell death , cell cycle , cancer research , apoptosis , genetics , dna , cancer
Chk2 is an effector kinase important for the activation of cell cycle checkpoints, p53, and apoptosis in response to DNA damage. Mus81 is required for the restart of stalled replication forks and for genomic integrity. Mus81 Δex3-4/Δex3-4 mice have increased cancer susceptibility that is exacerbated by p53 inactivation. In this study, we demonstrate that Chk2 inactivation impairs the development of Mus81 Δex3-4/Δex3-4 lymphoid cells in a cell-autonomous manner. Importantly, in contrast to its predicted tumor suppressor function, loss of Chk2 promotes mitotic catastrophe and cell death, and it results in suppressed oncogenic transformation and tumor development in Mus81 Δex3-4/Δex3-4 background. Thus, our data indicate that an important role for Chk2 is maintaining lymphocyte development and that dual inactivation of Chk2 and Mus81 remarkably inhibits cancer.