Activation-Induced Cytidine Deaminase Targets DNA at Sites of RNA Polymerase II Stalling by Interaction with Spt5

被引：290

作者：

Pavri, Rushad ^{[1
]}

Gazumyan, Anna ^{[1
,2
]}

Jankovic, Mila ^{[1
]}

Di Virgilio, Michela ^{[1
]}

Klein, Isaac ^{[1
]}

Ansarah-Sobrinho, Camilo ^{[3
]}

Resch, Wolfgang ^{[3
]}

Yamane, Arito ^{[3
]}

San-Martin, Bernardo Reina ^{[1
,4
]}

Barreto, Vasco ^{[1
,5
]}

Nieland, Thomas J. ^{[6
]}

Root, David E.

Casellas, Rafael ^{[3
]}

Nussenzweig, Michel C. ^{[1
,2
]}

机构：

[1] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA

[2] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA

[3] NCI, Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Ctr Canc Res, Bethesda, MD 20892 USA

[4] Univ Strasbourg, INSERM U964, CNRS UMR7104, IGBMC, F-67404 Illkirch Graffenstaden, France

[5] Inst Gulbenkian Ciencias, Lab Epigenet Soma, P-2780156 Oeiras, Portugal

[6] MIT, Broad Inst, RNAi Platform, Cambridge, MA 02142 USA

来源：

CELL | 2010年 / 143卷 / 01期

关键词：

CLASS-SWITCH RECOMBINATION; SINGLE-STRANDED-DNA; TRANSCRIPTION ELONGATION-FACTOR; ANTIBODY DIVERSIFICATION ENZYME; PROTEIN-KINASE-A; CENTER B-CELLS; SOMATIC HYPERMUTATION; C-MYC; IMMUNOGLOBULIN GENES; P-TEFB;

D O I：

10.1016/j.cell.2010.09.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：122 / 133

页数：12

共 87 条

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