Regulation of immunoglobulin diversification pathways by AID in a transgenic mouse model.
Shansab, Maryam.
2011
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Abstract: The
activation-induced cytidine deaminase (AID) enzyme plays a central role in B-cell
diversification such as somatic hypermutation (SHM), immunoglobulin (Ig) V-gene
conversion, and class switch recombination (CSR). AID function has also been implicated
in chromosomal B-cell translocations between the c-myc oncogene and the immunoglobulin
heavy-chain (Igh) locus. The regulatory ... read moremechanisms that promote such vastly different
outcomes after AID deamination are not clear. To better understand AID-dependent
pathways, I have used a transgenic mouse, which carries an antibody (Ab) heavy chain
transgene, to monitor CSR, SHM, and Ig V-gene conversion. I have shown that
Igh/transgene translocations require AID and resemble interchromosomal CSR events,
although the recombination mechanism does not appear to involve trans-switching between
the transgene Smu region and the endogenous Smu region. Because trans-switching between
the same S regions would not generate a change in Ab class, these results suggest that
CSR may be regulated to maximize B-cell responses to antigens. My results also show
that, although Ig V-gene conversion is not detected at the transgene locus, the
transgene is capable of accumulating AID-induced mutations, which are dependent on the
function of the Base Excision Repair (BER) and Mismatch Repair (MMR) pathways. These
results indicate that Igh cis elements 5' of the Cmu gene are sufficient to promote the
mutagenic function of BER and MMR, and that missing cis elements downstream of the Cmu
gene probably function to recruit AID to Ig loci more efficiently, which in turn may be
needed for gene conversion. Furthermore, because double stranded DNA breaks (DSBs) may
be needed for Ig V-gene conversion, these results imply that the extent of DNA damage
may dictate how the damage is resolved. Finally, I show that p21 is dispensable for SHM
and CSR. Together, my results indicate that one of the functions of the Ig regulatory
elements may be to make AID deamination more efficient, which in turn, may determine how
AID-induced DNA damage is resolved.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Immunology.
Advisors: Erik Selsing, and Naomi Rosenberg.
Committee: Peter Brodeur, and Henry Wortis.
Keyword: Immunology.read less - ID:
- kw52jm28b
- Component ID:
- tufts:20560
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- TARC Citation Guide EndNote
