Strand-biased spreading of mutations during somatic hypermutation.
Somatic hypermutation (SHM) is a major means by which diversity is achieved in antibody genes, and it is initiated by the deamination of cytosines to uracils in DNA by activation-induced deaminase (AID). However, the process that leads from these initiating deamination events to mutations at other residues remains poorly understood. We demonstrate that a single cytosine on the top (nontemplate) strand is sufficient to recruit AID and lead to mutations of upstream and downstream A/T residues. In contrast, the targeting of cytosines on the bottom strand by AID does not lead to substantial mutation of neighboring residues. This strand asymmetry is eliminated in mice deficient in mismatch repair, indicating that the error-prone mismatch repair machinery preferentially targets top-strand uracils in a way that promotes SHM during the antibody response.
Unniraman
Shyam
S
Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
Schatz
David G
DG
D000225:Adenine / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000378:metabolism*; D003596:Cytosine / Q000378:metabolism*; D053843:DNA Mismatch Repair; D003641:Deamination; D005803:Genes, Immunoglobulin; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D027041:Somatic Hypermutation, Immunoglobulin; D013941:Thymine / Q000378:metabolism; D019076:Transgenes; D014498:Uracil / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D014498:Uracil; D003596:Cytosine; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D000225:Adenine; D013941:Thymine