Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation

Kevin M. McBride; Anna Gazumyan; Eileen M. Woo; Vasco M. Barreto; Davide F. Robbiani; Brian T. Chait; Michel C. Nussenzweig

doi:10.1073/pnas.0603272103

Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation

Kevin M. McBride, Anna Gazumyan, Eileen M. Woo, Vasco M. Barreto, Davide F. Robbiani, Brian T. Chait, Michel C. Nussenzweig

Research output: Contribution to journal › Article › peer-review

123 Citations (Scopus)

Abstract

Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation of AID is important for maintaining genomic stability. In addition to transcriptional regulation, it has been proposed that phosphorylation can also modulate AID activity. Using a combination of MS and immunochemical approaches we found that 5-15% of the AID expressed in activated B cells was phosphorylated at serine-38 (p38AID). This form of AID was enriched in the chromatin fraction in activated B cells, suggesting a role for phosphorylation in targeting AID to DNA. Consistent with this idea, serine-38 to alanine mutant AID (AID ^538A) showed diminished somatic hypermutation activity on artificial and physiological DNA targets. We conclude that a small fraction of AID is phosphorylated in activated B cells and that the modified form contributes disproportionately to hypermutation.

Original language	English
Pages (from-to)	8798-8803
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	23
DOIs	https://doi.org/10.1073/pnas.0603272103
Publication status	Published - 6 Jun 2006
Externally published	Yes

Keywords

B cells
Class switch recombination
Protein kinase A
Somatic hypermutation

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title = "Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation",

abstract = "Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation of AID is important for maintaining genomic stability. In addition to transcriptional regulation, it has been proposed that phosphorylation can also modulate AID activity. Using a combination of MS and immunochemical approaches we found that 5-15% of the AID expressed in activated B cells was phosphorylated at serine-38 (p38AID). This form of AID was enriched in the chromatin fraction in activated B cells, suggesting a role for phosphorylation in targeting AID to DNA. Consistent with this idea, serine-38 to alanine mutant AID (AID 538A) showed diminished somatic hypermutation activity on artificial and physiological DNA targets. We conclude that a small fraction of AID is phosphorylated in activated B cells and that the modified form contributes disproportionately to hypermutation.",

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T1 - Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation

AU - McBride, Kevin M.

AU - Gazumyan, Anna

AU - Woo, Eileen M.

AU - Barreto, Vasco M.

AU - Robbiani, Davide F.

AU - Chait, Brian T.

AU - Nussenzweig, Michel C.

PY - 2006/6/6

Y1 - 2006/6/6

N2 - Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation of AID is important for maintaining genomic stability. In addition to transcriptional regulation, it has been proposed that phosphorylation can also modulate AID activity. Using a combination of MS and immunochemical approaches we found that 5-15% of the AID expressed in activated B cells was phosphorylated at serine-38 (p38AID). This form of AID was enriched in the chromatin fraction in activated B cells, suggesting a role for phosphorylation in targeting AID to DNA. Consistent with this idea, serine-38 to alanine mutant AID (AID 538A) showed diminished somatic hypermutation activity on artificial and physiological DNA targets. We conclude that a small fraction of AID is phosphorylated in activated B cells and that the modified form contributes disproportionately to hypermutation.

AB - Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation of AID is important for maintaining genomic stability. In addition to transcriptional regulation, it has been proposed that phosphorylation can also modulate AID activity. Using a combination of MS and immunochemical approaches we found that 5-15% of the AID expressed in activated B cells was phosphorylated at serine-38 (p38AID). This form of AID was enriched in the chromatin fraction in activated B cells, suggesting a role for phosphorylation in targeting AID to DNA. Consistent with this idea, serine-38 to alanine mutant AID (AID 538A) showed diminished somatic hypermutation activity on artificial and physiological DNA targets. We conclude that a small fraction of AID is phosphorylated in activated B cells and that the modified form contributes disproportionately to hypermutation.

KW - B cells

KW - Class switch recombination

KW - Protein kinase A

KW - Somatic hypermutation

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Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation

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