生命学院学术报告

题目：ATM prevents RAG-initiated double-stranded breaks to form dicentric chromosomes that lead to B cell lymphomas

报告人：Jiazhi Hu, Ph.D.

Research Fellow in Dr. Frederick Alt’s lab

Boston Children’s Hospital

报告时间：4月12日下午13:30

报告地点：新生物楼311

Abstract:

ATM is the master kinase responding to DNA double-stranded breaks (DSBs). In the absence of ATM, DSBs can persist and form translocations that participate in tumorigenesis. We generated mouse models recurrently developing B cell lymphomas in the absence of ATM, and found all the tumors arose from dicentric chromosomes involving RAG-generated DSBs in the IgH locus. We employed a high-throughput sequencing method to track DSBs in the ATM-deficient cells, and found ATM DNA damage response pathway could tether broken ends from the same DSBs together to facilitate their re-joining, and thus prevented the forming of translocations including dicentric chromosomes. In addition, we found that the RAG endonuclease, which is essential for V(D)J recombination, could generate numerous “off-target” cleavages in the genome; however, this “off-target” activity was restricted by genome-wide topologically-associated domains (TADs). We further proposed a linear-tracking model of RAG to explain the joining profiles of RAG-initiated DSBs.

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