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Molecular and Cellular Biology, April 2008, p. 2295-2303, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.02139-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Homologous Recombination Is Necessary for Normal Lymphocyte Development{triangledown}

Lura B. Caddle,{dagger} Muneer G. Hasham,{dagger} William H. Schott, Bobbi-Jo Shirley, and Kevin D. Mills*

The Jackson Laboratory, Bar Harbor, Maine 04609

Received 30 November 2007/ Accepted 8 January 2008

Primary immunodeficiencies are rare but serious diseases with diverse genetic causes. Accumulating evidence suggests that defects in DNA double-strand break (DSB) repair can underlie many of these syndromes. In this context, the nonhomologous end joining pathway of DSB repair is absolutely required for lymphoid development, but possible roles for the homologous recombination (HR) pathway have remained more controversial. While recent evidence suggests that HR may indeed be important to suppress lymphoid transformation, the specific relationship of HR to normal lymphocyte development remains unclear. We have investigated roles of the X-ray cross-complementing 2 (Xrcc2) HR gene in lymphocyte development. We show that HR is critical for normal B-cell development, with Xrcc2 nullizygosity leading to p53-dependent early S-phase arrest. In the absence of p53 (encoded by Trp53), Xrcc2-null B cells can fully develop but show high rates of chromosome and chromatid fragmentation. We present a molecular model wherein Xrcc2 is important to preserve or restore replication forks during rapid clonal expansion of developing lymphocytes. Our findings demonstrate a key role for HR in lymphoid development and suggest that Xrcc2 defects could underlie some human primary immunodeficiencies.

* Corresponding author. Mailing address: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. Phone: (207) 288-6820. Fax: (207) 288-6073. E-mail: kevin.mills{at}jax.org

{triangledown} Published ahead of print on 22 January 2008.

{dagger} L.B.C. and M.G.H. made equal contributions to this article.

Molecular and Cellular Biology, April 2008, p. 2295-2303, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.02139-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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