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

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

doi:10.1101/gad.275453.115

Theodoros Kantidakis, Nik Matthews + Show 10 more

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https://doi.org/10.1101/gad.275453.115

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Journal: Genes & development	Publication Date: Feb 15, 2016
Citations: 145	License type: cc-by

Affiliation: The Francis Crick Institute, TU Dresden

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.

Highlights

Genome instability is a recurring feature of tumorigenesis
We recently reported that RECQL5, a member of the RECQ family of helicases, is a general RNA polymerase II (RNAPII) elongation factor that is important for preserving genomic stability during transcription (Saponaro et al 2014)
Recent genome-wide cancer studies have shown that MLL2 is a tumor suppressor that is mutated in a large number of different cancers

Summary

Introduction

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. In the absence of tightly regulated cotranscriptional chromatin rearrangement, transcript elongation can be interrupted, resulting in transcription stress and potential disturbance of the integrity of the transcribed region (Svejstrup 2007; Selth et al 2010; Saponaro et al 2014). In light of these considerations, it is intriguing that mutations in chromatin-regulating enzymes have been identified in several recent cancer genome-sequencing projects (for recent reviews, see Roy et al 2014; Van Rechem and Whetstine 2014). These include diffuse large B-cell lymphoma (Pasqualucci et al 2011), follicular lymphoma (Okosun et al 2014), medulloblastoma (Parsons et al 2011; Pugh et al 2012), pediatric cancers (Huether et al 2014), breast cancer (Stephens et al 2012), lung carcinomas (The Cancer Genome Atlas Research Network 2012; Ross et al 2014; Yin et al 2014), parathyroid carcinoma (Kasaian et al 2013), esophageal squamous cell carcinoma (Gao et al 2014; Song et al 2014), head and neck squamous carcinomas (Seiwert et al 2015), renal carcinoma (Dalgliesh et al 2010), urothelial bladder carcinoma (Balbas-Martinez et al 2013), and prostate cancer (Grasso et al 2012)

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