RESUMO
How spatial chromosome organization influences genome integrity is still poorly understood. Here, we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CCCTC-binding factor (CTCF) and cohesin-bound sites at the bases of chromatin loops, and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hotspots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability and are key contributors to the occurrence of genome rearrangements that drive cancer.
Assuntos
DNA Topoisomerases Tipo II/genética , Instabilidade Genômica/genética , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Translocação Genética/genética , Fator de Ligação a CCCTC/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/química , Cromatina/genética , Cromossomos/química , Cromossomos/genética , DNA/genética , Quebras de DNA de Cadeia Dupla , Humanos , Leucemia/genética , Leucemia/patologiaRESUMO
Illegitimate joining of chromosome breaks can lead to the formation of chromosome translocations, a catastrophic type of genome rearrangements that often plays key roles in tumorigenesis. Emerging evidence suggests that the mobility of broken DNA loci can be an important determinant in partner search and clustering of individual breaks, events that can influence translocation frequency. We summarize here the recent literature on the mechanisms that regulate chromatin movement, focusing on studies exploring the motion properties of double-strand breaks in the context of chromatin, the functional consequences for DNA repair, and the formation of chromosome fusions.