Mutation of cancer driver MLL2 results in transcription stress and genome instability
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Mutation of cancer driver MLL2 results in transcription stress and genome instability. / Kantidakis, Theodoros; Saponaro, Marco; Mitter, Richard; Horswell, Stuart; Kranz, Andrea; Boeing, Stefan; Aygün, Ozan; Kelly, Gavin P.; Matthews, Nik; Stewart, Aengus; Stewart, A. Francis; Svejstrup, Jesper Q.
I: Genes and Development, Bind 30, 2016, s. 408-420.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Mutation of cancer driver MLL2 results in transcription stress and genome instability
AU - Kantidakis, Theodoros
AU - Saponaro, Marco
AU - Mitter, Richard
AU - Horswell, Stuart
AU - Kranz, Andrea
AU - Boeing, Stefan
AU - Aygün, Ozan
AU - Kelly, Gavin P.
AU - Matthews, Nik
AU - Stewart, Aengus
AU - Stewart, A. Francis
AU - Svejstrup, Jesper Q.
N1 - Publisher Copyright: © 2016 Kantidakis et al.
PY - 2016
Y1 - 2016
N2 - 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 ofγH2AX, 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.
AB - 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 ofγH2AX, 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.
KW - Cancer
KW - Genomic instability
KW - KMT2D
KW - MLL2
KW - Mutation
KW - Transcription
U2 - 10.1101/gad.275453.115
DO - 10.1101/gad.275453.115
M3 - Journal article
C2 - 26883360
AN - SCOPUS:84958958676
VL - 30
SP - 408
EP - 420
JO - Genes & Development
JF - Genes & Development
SN - 0890-9369
ER -
ID: 330898772