Activation-induced deaminase (AID) is an enzyme that mutates genes for antibodies in vertebrates. These AID-mediated mutations are necessary for an organism to generate specific antibodies to recognize and eradicate great varieties of microbial infections. However, if AID is not properly regulated, it can change DNA sequences of genes important for normal cell functions and cause diseases. Indeed, some lymphomas and leukemias are caused by abnormal activities of AID. How AID can change DNA sequences only in antibody genes but not in other genes is poorly understood. Recently, the catenin 2 like 1 protein (CTNNBL1) has been found to physically interact with AID. Little is known for the physiologic function of CTNNBL1. However, the interaction with CTNNBL1 is required for AID to change DNA sequences specifically in the antibody genes. In this study, a combination of high throughput approaches including next-generation sequencing and microarray analyses and targeted biochemical and immunologic analyses will be used to investigate how AID specifically mutate antibody genes, particularly what genomic regions are accessible to AID, both in the presence and in the absence of CTNNBL1. These experiments will also detect any alterations in transcription and splicing caused by the absence of CTNNBL1, and thereby shed lights on normal cellular functions of CTNNBL1. Mass spectrometry, mutagenic analyses and immunologic experiments will be performed to determine the molecular details of the interaction between AID and CTNNBL1 as well as to elucidate the mechanisms by which CTNNBL1 regulates the targeted activity of AID. It is anticipated that results from this study will be highly relevant for understanding the mechanisms underlying the generation of antibody diversity, and in the creation of new therapeutic strategies to minimize genomic disorders and cancers.
AID (activation-induced deaminase) is the DNA mutating enzyme responsible for changes of the antibody genes to generate different antibodies, but untimely or accidental actions of AID on cellular genes can cause cancers, immune-mediated or genetic diseases. The goal of this fellowship is to find out how AID is finely controlled to introduce mutations on genes for antibodies against microbes but not undesirable and harmful changes on genes of regular functions. Knowledge gained from this study will help understanding normal immune functions and facilitate the creation of new therapeutic strategies to minimize diseases such as cancers.
|Taylor, Benjamin Jm; Nik-Zainal, Serena; Wu, Yee Ling et al. (2013) DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. Elife 2:e00534|