Project Details
Abstract
Efficient humoral immune responses rely on the generation of high-affinity antibodies by a
process called affinity maturation. This involves an iterative mechanism in which somatic
hypermutation (SHM) and/or immunoglobulin gene conversion (GCV) generate random point mutations in
immunoglobulin (Ig) genes, and a subsequent selection step ensures the survival of cells encoding
high affinity antibodies. SHM and GCV are both initiated by
activation-induced cytidine deaminase (AID) creating U:G mismatches that are subsequently fixed by
mutagenic repair pathways. How these mutagenic activities are focused selectively on Ig genes
had been the topic of intense research efforts for more than a decade. We recently discovered
that SHM/GCV activity is focused to Ig loci by cis-regulatory DNA sequences named targeting
elements. Using chicken DT40 cells as our model system we showed that these elements are
distinct from classical transcriptional enhancers, and hence named them mutation enhancer elements
(MEEs). This proposal is now aimed at understanding a fundamental question in the field: how do
these MEEs function? We will focus on one specific element, the 3′MEE in the chicken IGL locus,
and try to (1) identify the trans-acting factors that bind to it, their binding sites, and (2)
determine whether this elements recruits AID activity or induces error-prone DNA repair.
Furthermore, we will expand our work to human and mouse Ig genes and identify the MEEs in these
loci. Combined our proposed studies will provide knowledge that is critical for understanding the
role of these MEEs in human health and disease, and start to reveal the role of cis-regulatory
sequences in controlling genome integrity.
Project IDs
Project ID:PC10705-0234
External Project ID:MOST102-2320-B182-001-MY3
External Project ID:MOST102-2320-B182-001-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/14 → 31/07/15 |
Keywords
- Somatic hypermutation
- gene conversion
- AID
- DNA repair
- mutagenesis
- enhancers
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