Mutation of cancer driverMLL2results in transcription stress and genome instability

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.

Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses

“…In fact, γ-H2AX modification is strongly diminished over highly transcribed genes in yeast (Lee et al, 2014) and we achieved much higher transcription levels with the mAIRN CD cells than with the mAIRN HO cells (Figure 1C). Studies with human cells, however, suggest γ-H2AX can still be enriched at highly expressed regions on the genome (Kantidakis et al, 2016; Tuduri et al, 2009), so our data may be explained by less stably assembled chromatin on the plasmid than on the genome.…”

Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent copy number variation in IPO11 and prognostic significance of importin-11 overexpression on poor survival

“…For example, we identified four genes (MLL2, SUGP2, TP53 and TTN) with recurrent functional mutations in the comparison of superficial tumor tissues with normal tissues. MLL2 is a histone methyltransferase that is part of a large protein complex, ASCOM, that regulates transcription of the β-globin and estrogen receptor genes [13], and recent evidence indicates that MLL2 mutations result in genomic instability, which is a strong driver of tumorigenesis [14]. In our study, we found that 2/3 subjects harbored a frameshift deletion in MLL2, indicating that MLL2 probably also plays a role in tumorigenesis in BCa.…”

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

“…Despite the hope for new targeted therapies, mechanisms for resistance to inhibitors of BET (31, 47, 48) or ATR (18) have been recently uncovered. Interestingly, perturbing the chromatin-related functions of MLL proteins has been shown to lead to DNA replication stress (33, 49). In this context, a combination of RSR inhibitors, leading to p53-independent toxicity, and epigenetic inhibitors that may both interfere with the transcriptional properties of the MLL fusion protein and further increase the levels of replication stress, could help overcome the resistance of MLL-driven AML to chemotherapy.…”