TY - CHAP
T1 - Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism
AU - Chaudhuri, Jayanta
AU - Basu, Uttiya
AU - Zarrin, Ali
AU - Yan, Catherine
AU - Franco, Sonia
AU - Perlot, Thomas
AU - Vuong, Bao
AU - Wang, Jing
AU - Phan, Ryan T.
AU - Datta, Abhishek
AU - Manis, John
AU - Alt, Frederick W.
N1 - Funding Information:
We thank Michael Neuberger for critically reviewing sections of this chapter. J.C. is a Damon Runyon Scholar, U.B. is a fellow of the Irvington Institute, A.D. is a Leukemia Research Foundation Fellow, R.T.P. is a fellow of the Cancer Research Institute, B.V. is supported by a training grant from the NIH. F.W.A is an investigator of the Howard Hughes Medical Institute. This work is supported by NIH grants CA92625, CA109901, and AI31541 to F.W.A.
PY - 2007
Y1 - 2007
N2 - To mount an optimum immune response, mature B lymphocytes can change the class of expressed antibody from IgM to IgG, IgA, or IgE through a recombination/deletion process termed immunoglobulin heavy chain (IgH) class switch recombination (CSR). CSR requires the activation-induced cytidine deaminase (AID), which has been shown to employ single-stranded DNA as a substrate in vitro. IgH CSR occurs within and requires large, repetitive sequences, termed S regions, which are parts of germ line transcription units (termed "CH genes") that are composed of promoters, S regions, and individual IgH constant region exons. CSR requires and is directed by germ line transcription of participating CH genes prior to CSR. AID deamination of cytidines in S regions appears to lead to S region double-stranded breaks (DSBs) required to initiate CSR. Joining of two broken S regions to complete CSR exploits the activities of general DNA DSB repair mechanisms. In this chapter, we discuss our current knowledge of the function of S regions, germ line transcription, AID, and DNA repair in CSR. We present a model for CSR in which transcription through S regions provides DNA substrates on which AID can generate DSB-inducing lesions. We also discuss how phosphorylation of AID may mediate interactions with cofactors that facilitate access to transcribed S regions during CSR and transcribed variable regions during the related process of somatic hypermutation (SHM). Finally, in the context of this CSR model, we further discuss current findings that suggest synapsis and joining of S region DSBs during CSR have evolved to exploit general mechanisms that function to join widely separated chromosomal DSBs.
AB - To mount an optimum immune response, mature B lymphocytes can change the class of expressed antibody from IgM to IgG, IgA, or IgE through a recombination/deletion process termed immunoglobulin heavy chain (IgH) class switch recombination (CSR). CSR requires the activation-induced cytidine deaminase (AID), which has been shown to employ single-stranded DNA as a substrate in vitro. IgH CSR occurs within and requires large, repetitive sequences, termed S regions, which are parts of germ line transcription units (termed "CH genes") that are composed of promoters, S regions, and individual IgH constant region exons. CSR requires and is directed by germ line transcription of participating CH genes prior to CSR. AID deamination of cytidines in S regions appears to lead to S region double-stranded breaks (DSBs) required to initiate CSR. Joining of two broken S regions to complete CSR exploits the activities of general DNA DSB repair mechanisms. In this chapter, we discuss our current knowledge of the function of S regions, germ line transcription, AID, and DNA repair in CSR. We present a model for CSR in which transcription through S regions provides DNA substrates on which AID can generate DSB-inducing lesions. We also discuss how phosphorylation of AID may mediate interactions with cofactors that facilitate access to transcribed S regions during CSR and transcribed variable regions during the related process of somatic hypermutation (SHM). Finally, in the context of this CSR model, we further discuss current findings that suggest synapsis and joining of S region DSBs during CSR have evolved to exploit general mechanisms that function to join widely separated chromosomal DSBs.
UR - http://www.scopus.com/inward/record.url?scp=34249794280&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249794280&partnerID=8YFLogxK
U2 - 10.1016/S0065-2776(06)94006-1
DO - 10.1016/S0065-2776(06)94006-1
M3 - Chapter
C2 - 17560275
AN - SCOPUS:34249794280
SN - 0123737060
SN - 9780123737069
T3 - Advances in Immunology
SP - 157
EP - 214
BT - AID for Immunoglobulin Diversity
A2 - Alt, Frederick
A2 - Honjo, Tasuku
ER -