Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells

被引：362

作者：

Chiarle, Roberto ^{[1
,2
,3
,4
,5
]}

Zhang, Yu ^{[1
,2
,3
]}

Frock, Richard L. ^{[1
,2
,3
]}

Lewis, Susanna M. ^{[1
,2
,3
]}

Molinie, Benoit ^{[6
]}

Ho, Yu-Jui ^{[1
,2
,3
]}

Myers, Darienne R. ^{[1
,2
,3
]}

Choi, Vivian W. ^{[1
,2
,3
]}

Compagno, Mara ^{[1
,2
,3
,4
,5
]}

Malkin, Daniel J. ^{[1
,2
,3
]}

Neuberg, Donna ^{[7
]}

Monti, Stefano ^{[8
,9
]}

Giallourakis, Cosmas C. ^{[6
]}

Gostissa, Monica ^{[1
,2
,3
]}

Alt, Frederick W. ^{[1
,2
,3
]}

机构：

[1] Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[4] Univ Turin, Dept Biomed Sci & Human Oncol, I-10126 Turin, Italy

[5] Univ Turin, CERMS, I-10126 Turin, Italy

[6] Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA

[7] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA

[8] 5 Cambridge Ctr, Broad Inst, Cambridge, MA 02142 USA

[9] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02118 USA

来源：

CELL | 2011年 / 147卷 / 01期

基金：

欧洲研究理事会;

关键词：

END-JOINING PATHWAY; CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; DNA BREAKS; C-MYC; HYPERMUTATION; LYMPHOCYTES; CANCER; IDENTIFICATION; TRANSCRIPTION;

D O I：

10.1016/j.cell.2011.07.049

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：

Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeting. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics.

引用

页码：107 / 119

页数：13

共 46 条

[1] The connection between transcription and genomic instability [J].