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Molecular and Cellular Biology, March 2003, p. 1666-1673, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1666-1673.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

BRCT Domain-Containing Protein PTIP Is Essential for Progression through Mitosis

Eun Ah Cho,1 Marc J. Prindle,2 and Gregory R. Dressler1*

Department of Pathology,1 Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, Michigan 481092

Received 30 July 2002/ Returned for modification 21 August 2002/ Accepted 13 December 2002

The Pax transactivation domain-interacting protein (PTIP) is a large nuclear protein with multiple BRCT domains that was identified on the basis of its interaction with transcription factors of the Pax and Smad families. To address the function of PTIP during mouse development, we generated a constitutive null allele. Homozygous PTIP mutants are developmentally retarded, disorganized, and embryonic lethal by day 9.5 of embryonic development (E9.5). PTIP mutant cells appear to replicate DNA but show reduced levels of mitosis and widespread cell death by E8.5. DNA damage appears to precede nuclear condensation at E7.5, suggesting a defect in DNA repair. Neither embryonic fibroblast nor embryonic stem cells from PTIP mutants proliferate in culture, suggesting a fundamental defect in cell proliferation. Trophoblast cells from PTIP mutants are more sensitive to DNA-damaging agents. Condensation of chromatin and expression of phospho-histone H3 are also affected in PTIP mutants, and this may underlie the inability of PTIP mutants to progress through mitosis. Given the role of BRCT domain proteins in DNA repair and cell cycle control, we propose that PTIP is an essential element of the cell proliferation machinery, perhaps by functioning in the DNA repair pathways.

* Corresponding author. Mailing address: 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0650. Phone: (734) 764-6490. Fax: (734) 763-6640. E-mail: Dressler{at}umich.edu.

Molecular and Cellular Biology, March 2003, p. 1666-1673, Vol. 23, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.5.1666-1673.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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