Homologous recombination is necessary for normal lymphocyte development.

Molecular and Cellular Biology
L B CaddleK D Mills

Abstract

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 unde...Continue Reading

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Citations

Apr 17, 2013·The Journal of Experimental Medicine·Kristin R LamontKevin D Mills
Jul 19, 2016·The Journal of Clinical Investigation·Saskia N van der CrabbenGijs van Haaften
Sep 6, 2018·Cancer Biology & Therapy·John J WilsonMuneer G Hasham
Jul 25, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Muneer G HashamKevin D Mills
Aug 11, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Gianna HirthBerit Jungnickel
Oct 11, 2021·Journal of Clinical Immunology·Parisa AmirifarAsghar Aghamohammadi

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