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Inactivation of chk2 and mus81 leads to impaired lymphocytes development, reduced genomic instability, and suppression of cancer.

ABSTRACT: 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(?ex3-4/?ex3-4) mice have increased cancer susceptibility that is exacerbated by p53 inactivation. In this study, we demonstrate that Chk2 inactivation impairs the development of Mus81(?ex3-4/?ex3-4) 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(?ex3-4/?ex3-4) 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.

SUBMITTER: El Ghamrasni S 

PROVIDER: S-EPMC3098187 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Inactivation of chk2 and mus81 leads to impaired lymphocytes development, reduced genomic instability, and suppression of cancer.

El Ghamrasni Samah S   Pamidi Ashwin A   Halaby Marie Jo MJ   Bohgaki Miyuki M   Cardoso Renato R   Li Li L   Venkatesan Shriram S   Sethu Swaminathan S   Hirao Atsushi A   Mak Tak W TW   Hande Manoor Prakash MP   Hakem Anne A   Hakem Razqallah R  

PLoS genetics 20110519 5

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  ...[more]

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