Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells.-猫眼课题宝

DOI：

10.1016/j.cell.2011.07.049

发表时间：

2011-09-30

期刊：

Cell

影响因子：

64.5

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Chiarle R;Zhang Y;Frock RL;Lewis SM;Molinie B;Ho YJ;Myers DR;Choi VW;Compagno M;Malkin DJ;Neuberg D;Monti S;Giallourakis CC;Gostissa M;Alt FW

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186939/?report=classic

While 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 very widely across the genome, but were preferentially targeted to transcribed chromosomal regions and also to numerous AID-dependent and AID-independent hotspots, with the latter being comprised mainly of cryptic genomic 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 micro-homologies. We discuss implications of our findings for diverse fields including gene therapy and cancer genomics.