title: Mutation of cancer driver MLL2 results in transcription stress and genome instability.
abstract: Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, although MLL2 mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly, MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γH2AX, and suffer frequent mutation. The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis.
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kantidakis
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Marco
authors.initials: M
authors.lastname: Saponaro
authors.affiliation: Bioinformatics and Biostatistics Group, The Francis Crick Institute, London WC2A 3LY, United Kingdom;
authors.forename: Richard
authors.initials: R
authors.lastname: Mitter
authors.affiliation: Bioinformatics and Biostatistics Group, The Francis Crick Institute, London WC2A 3LY, United Kingdom;
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.affiliation: Biotechnologisches Zentrum, Technische Universität Dresden, 01062 Dresden, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Kranz
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Stefan
authors.initials: S
authors.lastname: Boeing
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Ozan
authors.initials: O
authors.lastname: Aygün
authors.affiliation: Bioinformatics and Biostatistics Group, The Francis Crick Institute, London WC2A 3LY, United Kingdom;
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Kelly
authors.affiliation: Advanced Sequencing Facility, The Francis Crick Institute, London WC2A 3LY, United Kingdom.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: Bioinformatics and Biostatistics Group, The Francis Crick Institute, London WC2A 3LY, United Kingdom;
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Biotechnologisches Zentrum, Technische Universität Dresden, 01062 Dresden, Germany;
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;
authors.forename: Jesper Q
authors.initials: JQ
authors.lastname: Svejstrup
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D053484:RecQ Helicases / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse; D012319:RNA Polymerase II; D053484:RecQ Helicases; C501069:Recql5 protein, mouse
keywords: KMT2D; MLL2; cancer; genomic instability; mutation; transcription