Project description:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT.
Project description:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CTCF and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy concomitantly rewire DNA cleavage sites to novel contact domain boundaries. While transcription and replication coupled genomic rearrangements have been well documented, we demonstrate that DSBs at loop anchors are transcription-, replication-, and cell type- independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in acute leukemias and prostate cancers. Thus, loop anchors serve as preferred and promiscuous fragile sites that generate DSBs and chromosomal rearrangements.
Project description:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CTCF and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy concomitantly rewire DNA cleavage sites to novel contact domain boundaries. While transcription and replication coupled genomic rearrangements have been well documented, we demonstrate that DSBs at loop anchors are transcription-, replication-, and cell type- independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in acute leukemias and prostate cancers. Thus, loop anchors serve as preferred and promiscuous fragile sites that generate DSBs and chromosomal rearrangements.
Project description:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CTCF and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy concomitantly rewire DNA cleavage sites to novel contact domain boundaries. While transcription and replication coupled genomic rearrangements have been well documented, we demonstrate that DSBs at loop anchors are transcription-, replication-, and cell type- independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in acute leukemias and prostate cancers. Thus, loop anchors serve as preferred and promiscuous fragile sites that generate DSBs and chromosomal rearrangements.