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Antigen receptor allelic exclusion is achieved through incompletely defined mechanisms that promote asynchronous
initiation and subsequent feedback inhibition of V-to-(D)J recombination between antigen receptor loci on homologous
chromosomes. The original feedback inhibition model speculated that Ig
k
recombination events on one allele might activate
signals that transiently suppress additional rearrangements on the other allele. DNA cleavage activates the DNA-dependent
protein kinase (DNA-PK) near DNA breaks and the Ataxia Telangiectasia mutated (ATM) kinase throughout the nucleus. ATM
phosphorylation of histone H2AX along broken DNA strands creates high-density binding sites for MDC1, which functions with
H2AX to amplify some ATM signals by retaining ATM kinases in chromatin at DSBs. We have found in primary mouse pre-B
cells that inactivation of ATM, but not DNA-PK, H2AX, or MDC1, leads to increased cleavage of Ig
k
alleles and 3?J
k
segments
independent of defects in coding join formation. This inhibition of Ig
k
recombination correlates with ATM-dependent repression
of Rag1 mRNA levels. We have shown that inactivation of ATM, but neither H2AX nor MDC1, causes a higher frequency of
B cells exhibiting Ig
k
allelic inclusion. Collectively, our findings suggest that the soluble pool of ATM kinases activated by Ig
k
cleavage transduces signals that suppress the initiation of additional V
k
-to-J
k
recombination events, and thereby helps enforce
Ig
k
allelic exclusion.
Biography
Craig Bassing earned his Ph.D. from the Duke University School of Medicine under the mentorship of Dr. Xiao-Fan Wang. Dr. Bassing then trained
as a post-doctoral fellow at Harvard Medical School under the tutelage of Dr. Frederick W. Alt. In 2005, Dr. Bassing established his own research lab
at the Children?s Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania. Dr. Bassing is
an Associate Professor in the Department of Pathology and Laboratory Medicine, an Investigator of the Childhood Cancer Center, and an Associate
Member of the Abramson Family Cancer Research Institute.
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