title: Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes.
abstract: We show that the time required to transcribe human genes larger than 800 kb spans more than one complete cell cycle, while their transcription speed equals that of smaller genes. Independently of their expression status, we find the long genes to replicate late. Regions of concomitant transcription and replication in late S phase exhibit DNA break hot spots known as common fragile sites (CFSs). This CFS instability depends on the expression of the underlying long genes. We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability. In summary, our results show that, on the longest human genes, collisions of the transcription machinery with a replication fork are inevitable, creating R-loops and consequent CFS formation. Functional replication machinery needs to be involved in the resolution of conflicts between transcription and replication machineries to ensure genomic stability.
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, BP 10142-67404 ILLKIRCH Cedex, France. anneh@igbmc.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Helmrich
authors.forename: Monica
authors.initials: M
authors.lastname: Ballarino
authors.forename: Laszlo
authors.initials: L
authors.lastname: Tora
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D043283:Chromosome Fragile Sites / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005796:Genes / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D016914:Ribonuclease H / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D012313:RNA; D004247:DNA; D012319:RNA Polymerase II; C091139:ribonuclease HII; D016914:Ribonuclease H; D004264:DNA Topoisomerases, Type I