Postdoctoral Fellow

Immunobiology

Yale School of Medicine (New Haven, CT)

David G Schatz

Targeting Somatic Hypermutation

Somatic hypermutation (SHM) is a B cell specific genetic process that causes point mutations within the variable regions of the immunoglobulin (Ig) loci, and underlies the process of Ig affinity maturation. This mutagenic process is initiated at the Ig loci by the enzymatic activity of activation-induced cytosine deaminase (AID), which deaminates cytosine residues in the DNA to uracils. This is followed by the recruitment of error-prone base excision repair (BER) and/or mis-match repair (MMR) machineries that introduce mutations at or near the uracil residue. The error-prone nature of BER and MMR in resolving uracil residues at the Ig loci is in contrast to the high-fidelity repair these processes achieve while resolving uracil residues that arise in the genome spontaneously or as a result of mis-incorporation during replication. Not surprisingly, a major question in the field of SHM has been to determine how AID and the error-prone repair pathways are specifically targeted to the Ig loci, or alternatively stated, how the rest of the genome is shielded against the actions of this mutation inducing machinery.

A recent study published by Dr. David Schatz’s lab has revealed two key features of SHM regulation in mice – 1. In B cells, AID does not target genes as specifically as previously believed. Many transcribed non-Ig genes are ‘hit’ by AID eg. Bcl6, Myc, Cd83, Ocab etc. 2. Most of the mutations in these non-Ig genes are resolved by high-fidelity repair. This study underscores the importance of understanding how the specific recruitment of high-fidelity repair to the non-Ig genes is achieved such that these genes are protected from accumulating mutations that could lead to genomic instabilities and disease conditions like cancer. My project in the Schatz laboratory is aimed at understanding the molecular mechanisms that underlie the differential recruitment of high-fidelity and error-prone repair pathways to different genes during somatic hypermutation.