Journal
GENES & DEVELOPMENT
Volume 30, Issue 4, Pages 408-420Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.275453.115
Keywords
MLL2; KMT2D; genomic instability; transcription; cancer; mutation
Categories
Funding
- Francis Crick Institute [FCI01]
- Cancer Research UK
- UK Medical Research Council
- Wellcome Trust
- European Research Council
- Association for International Cancer Research
- Deutsche Krebshilfe
- Cancer Research UK [11567] Funding Source: researchfish
- The Francis Crick Institute [10166, 10490, 10168, 10002] Funding Source: researchfish
- Worldwide Cancer Research [09-0730] Funding Source: researchfish
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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 gamma H2AX, 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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