Mutation of cancer driver MLL2 results in transcription stress and genome instability
Name
Kantidakis-2016-Mutation of cancer d.pdf
Size
1.13 MB
Format
Adobe PDF
Checksum (MD5)
a8affbbc808394757abe3961c5cb5ab0
Author(s)
Kantidakis, Theodoros
Saponaro, Marco
Mitter, Richard
Horswell, Stuart
Kranz, Andrea
Boeing, Stefan
Aygun, Ozan
Kelly, Gavin P.
Matthews, Nik
Stewart, Aengus
Date Issued
February 2016
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Kantidakis, Theodoros, Marco Saponaro, Richard Mitter, Stuart Horswell, Andrea Kranz, Stefan Boeing, Ozan Aygün, Gavin P. Kelly, Nik Matthews, Aengus Stewart, A. Francis Stewart, and Jesper Q. Svejstrup. "Mutation of cancer driver MLL2 results in transcription stress and genome instability." Genes & Dev. (February 2016) 30:408-420.
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1101/gad.275453.115
