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Inactivation of CtIP Leads to Early Embryonic Lethality Mediated by G₁ Restraint and to Tumorigenesis by Haploid Insufficiency

Phang-Lang Chen,^1, Feng Liu,^1, Suna Cai,¹ Xiaoqin Lin,¹ Aihua Li,¹ Yumay Chen,² Bingnan Gu,¹ Eva Y.-H. P. Lee,¹ and Wen-Hwa Lee^1*

Department of Biological Chemistry, College of Medicine, University of California, Irvine, Irvine, California 92697,¹ Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245²

Received 16 November 2004/ Returned for modification 25 December 2004/ Accepted 3 February 2005

CtIP interacts with a group of tumor suppressor proteins including RB (retinoblastoma protein), BRCA1, Ikaros, and CtBP, which regulate cell cycle progression through transcriptional repression as well as chromatin remodeling. However, how CtIP exerts its biological function in cell cycle progression remains elusive. To address this issue, we generated an inactivated Ctip allele in mice by inserting a neo gene into exon 5. The corresponding Ctip^–/– embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G₁, leading to a slightly elevated cell death. Mouse NIH 3T3 cells depleted of Ctip were arrested at G₁ with the concomitant increase in hypophosphorylated Rb and Cdk inhibitors, p21. However, depletion of Ctip failed to arrest Rb^–/– mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G₁, suggesting that this arrest is RB dependent. Importantly, the life span of Ctip^+/– heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas. The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Taken together, this finding uncovers a novel G₁/S regulation in that CtIP counteracts Rb-mediated G₁ restraint. Deregulation of this function leads to a defect in early embryogenesis and contributes, in part, to tumor formation.

The first two authors contributed equally to this work.

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