Germinal center B cells undergo a high rate of somatic mutation and recombination of their immunoglobulin genes that is responsible for the affinity maturation and isotype switching that generates protective antibodies. These processes are initiated by activation induced cytidine deaminase which generates G:U mismatches that are processed by replication, base excision repair and mismatch repair to produce the mutations required for somatic hypermutation of antibody variable and switch regions. Mismatch repair is responsible for ~60% of the total mutations and most of the mutations in A:T bases that lead to production of more effective antibodies. While mismatch repair normally maintains the integrity and stability of the genome, at the Ig gene it mediates extensive mutation and recombination. Here we propose to examine how germinal center B cells use mismatch repair to recruit error prone repair to specific regions of the immunoglobulin genes while continuing to maintain genomic stability in the rest of genome and to examine role of mismatch repair in the B cell lymphomagenesis. We will do this by: 1) determining how MSH6 and the other mismatch repair proteins interact with PCNA to recruit error prone repair to the immunoglobulin variable and switch regions, but not to other genes in mutating and switching germinal center B cells;2) comparing the interactions of the mismatch repair proteins with each other and with other proteins in mutating and switching B cells and with those interactions in other types of cells;and 3) examining the characteristics of the lymphomas that arise in MSH6 deficient and mutant mice in order to understand how MSH6 protects B cells from lymphomagenesis.
To protect us from pathogenic organisms, it is necessary for us to produce antibodies to every possible antigen and to rapidly change those antibodies as the pathogen changes. We do this by introducing many mutations into the genes that encode the antibody molecules as we respond to infection and this genetic instability is accomplished mostly through a process called mismatch repair. We will use mice that have genetic defects in mismatch repair to examine how the generation of antibody diversity is accomplished.
|Wang, Xiaohua; Fan, Manxia; Kalis, Susan et al. (2014) A source of the single-stranded DNA substrate for activation-induced deaminase during somatic hypermutation. Nat Commun 5:4137|
|Jaszczur, Malgorzata; Bertram, Jeffrey G; Pham, Phuong et al. (2013) AID and Apobec3G haphazard deamination and mutational diversity. Cell Mol Life Sci 70:3089-108|
|Schaetzlein, Sonja; Chahwan, Richard; Avdievich, Elena et al. (2013) Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes. Proc Natl Acad Sci U S A 110:E2470-9|
|Chahwan, Richard; van Oers, Johanna M M; Avdievich, Elena et al. (2012) The ATPase activity of MLH1 is required to orchestrate DNA double-strand breaks and end processing during class switch recombination. J Exp Med 209:671-8|
|Chahwan, Richard; Edelmann, Winfried; Scharff, Matthew D et al. (2011) Mismatch-mediated error prone repair at the immunoglobulin genes. Biomed Pharmacother 65:529-36|
|Chahwan, Richard; Wontakal, Sandeep N; Roa, Sergio (2011) The multidimensional nature of epigenetic information and its role in disease. Discov Med 11:233-43|
|Baughn, Linda B; Kalis, Susan L; MacCarthy, Thomas et al. (2011) Recombinase-mediated cassette exchange as a novel method to study somatic hypermutation in Ramos cells. MBio 2:|
|Peled, Jonathan U; Sellers, Rani S; Iglesias-Ussel, Maria D et al. (2010) Msh6 protects mature B cells from lymphoma by preserving genomic stability. Am J Pathol 177:2597-608|
|Ramachandran, Shaliny; Chahwan, Richard; Nepal, Rajeev M et al. (2010) The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination. Proc Natl Acad Sci U S A 107:809-14|
|van Oers, Johanna M M; Roa, Sergio; Werling, Uwe et al. (2010) PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance. Proc Natl Acad Sci U S A 107:13384-9|
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