Mutation of cancer driver MLL2 results in transcription stress and genome instability

Theodoros Kantidakis, Marco Saponaro, Richard Mitter, Stuart Horswell, Andrea Kranz, Stefan Boeing, Ozan Aygun, Gavin P Kelly, Nik Matthews, Aengus Stewart, A Francis Stewart, Jesper Q Svejstrup

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65 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)408-420
Number of pages13
JournalGenes & Development
Issue number4
Publication statusPublished - 15 Feb 2016


  • MLL2
  • KMT2D
  • genomic instability
  • transcription
  • cancer
  • mutation


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