Mutation of cancer driverMLL2results in transcription stress and genome instability

Genes and Development - Tập 30 Số 4 - Trang 408-420 - 2016
Theodoros Kantidakis1, Marco Saponaro1, Richard Mitter2, Stuart Horswell2, Andrea Kranz3, Stefan Boeing1, Ozan Aygün1, Gavin Kelly2, Nik Matthews4, Aengus Stewart2, Jesper Q. Svejstrup1
11Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom
22Bioinformatics and Biostatistics Group, The Francis Crick Institute, London WC2A 3LY, United Kingdom
33Biotechnologisches Zentrum, Technische Universität Dresden, 01062 Dresden, Germany
44Advanced Sequencing Facility, The Francis Crick Institute, London WC2A 3LY, United Kingdom

Tóm tắt

Genome instability is a recurring feature of tumorigenesis. Mutation inMLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence thatMLL2mutation results in genome instability. Mouse cells in whichMLL2gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. HumanMLL2knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, althoughMLL2mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly,MLL2mutated 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.

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Genes and Development

Tập 30 Số 4

408-420

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