title: Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5.
abstract: Activation-induced cytidine deaminase (AID) initiates antibody gene diversification by creating U:G mismatches. However, AID is not specific for antibody genes; Off-target lesions can activate oncogenes or cause chromosome translocations. Despite its importance in these transactions little is known about how AID finds its targets. We performed an shRNA screen to identify factors required for class switch recombination (CSR) of antibody loci. We found that Spt5, a factor associated with stalled RNA polymerase II (Pol II) and single stranded DNA (ssDNA), is required for CSR. Spt5 interacts with AID, it facilitates association between AID and Pol II, and AID recruitment to its Ig and non-Ig targets. ChIP-seq experiments reveal that Spt5 colocalizes with AID and stalled Pol II. Further, Spt5 accumulation at sites of Pol II stalling is predictive of AID-induced mutation. We propose that AID is targeted to sites of Pol II stalling in part via its association with Spt5.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Rushad
authors.initials: R
authors.lastname: Pavri
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.forename: Mila
authors.initials: M
authors.lastname: Jankovic
authors.forename: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.forename: Isaac
authors.initials: I
authors.lastname: Klein
authors.forename: Camilo
authors.initials: C
authors.lastname: Ansarah-Sobrinho
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.forename: Bernardo
authors.initials: B
authors.lastname: Reina San-Martin
authors.forename: Vasco
authors.initials: V
authors.lastname: Barreto
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nieland
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching; D007136:Immunoglobulins / Q000235:genetics; D051379:Mice; D012319:RNA Polymerase II / Q000378:metabolism*; D035602:Transcriptional Elongation Factors / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D007136:Immunoglobulins; D035602:Transcriptional Elongation Factors; C069940:SPT5 transcriptional elongation factor; D012319:RNA Polymerase II; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase