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

Theodoros Kantidakis1, Marco Saponaro1, Richard Mitter2

  • 1Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms EN6 3LD, United Kingdom;

Genes & Development
|February 18, 2016
PubMed

Insights

Mutations in the MLL2 gene cause genome instability, a key factor in cancer development. This instability arises from transcription stress, impacting gene mutation and replication.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Genome instability is a hallmark of cancer.
  • Mutations in MLL2, a histone methyltransferase, are implicated in various cancers, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of MLL2 mutations in genome instability.
  • To elucidate the molecular mechanisms by which MLL2 mutations contribute to tumorigenesis.

Main Methods:

  • Induced MLL2 gene deletion in mouse cells.
  • Analysis of genome instability markers (sister chromatid exchange, chromosomal aberrations, 53BP1 foci, micronuclei).
  • Investigation of MLL2 interactions with RNA polymerase II (RNAPII) and RECQL5.
  • Assessment of H3K4me levels and transcription stress in MLL2-mutated cells.

Main Results:

  • MLL2 deletion in mouse cells and MLL2 knockout in human cells led to increased genome instability.
  • MLL2 interacts with RNAPII and RECQL5.
  • MLL2-mutated cells showed hypomethylation near RNAPII, signs of transcription stress, and mutations in early-replicating fragile sites.

Conclusions:

  • MLL2 is crucial for maintaining genome stability.
  • Transcription stress driven by MLL2 mutations is a significant factor in tumorigenesis.
  • Understanding MLL2's role provides insights into cancer development and potential therapeutic targets.
Keywords:
KMT2DMLL2cancergenomic instabilitymutationtranscription

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