NDLI: Target DNA sequence directly regulates the frequency of activation-induced deaminase-dependent mutations.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Chen, Zhangguo O'Connor, Brian P. Viboolsittiseri, Sawanee S. Wang, Jing H.
Description	Country affiliation: United States Author Affiliation: Chen Z ( Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, CO 80206, USA.)
Abstract	Activation-induced deaminase (AID) catalyses class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes to enhance Ab diversity. CSR involves breaking and rejoining highly repetitive switch (S) regions in the IgH (Igh) locus. S regions appear to be preferential targets of AID. To determine whether S region sequence per se, independent of Igh cis regulatory elements, can influence AID targeting efficiency and mutation frequency, we established a knock-in mouse model by inserting a core SÎ³1 region into the first intron of proto-oncogene Bcl6, which is a non-Ig target of SHM. We found that the mutation frequency of the inserted SÎ³1 region was dramatically higher than that of the adjacent Bcl6 endogenous sequence. Mechanistically, S region-enhanced SHM was associated with increased recruitment of AID and RNA polymerase II, together with Spt5, albeit to a lesser extent. Our studies demonstrate that target DNA sequences influence mutation frequency via regulating AID recruitment. We propose that the nucleotide sequence preference may serve as an additional layer of AID regulation by restricting its mutagenic activity to specific sequences despite the observation that AID has the potential to access the genome widely.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	8
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-10-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cytidine Deaminase Genetics Gene Knock-in Techniques Somatic Hypermutation, Immunoglobulin Animals Metabolism Dna Mutational Analysis Dna-binding Proteins Immunoglobulin Switch Region Mice Proto-oncogene Proteins C-bcl-6 Rna Polymerase Ii Recombination, Genetic Immunology Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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