The Lysine-specific Methyltransferase KMT2C/MLL3 Regulates DNA Repair Components in Cancer

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2019 Jan 23

PMID 30665945

Citations 78

Authors

Theodoros Rampias

Dimitris Karagiannis

Margaritis Avgeris

Alexander Polyzos

Antonis Kokkalis

Zoi Kanaki

Evgenia Kousidou

Maria Tzetis

Emmanouil Kanavakis

Konstantinos Stravodimos

Kalliopi N Manola

Gabriel E Pantelias

Andreas Scorilas

Apostolos Klinakis

Affiliations

Soon will be listed here.

Abstract

Genome-wide studies in tumor cells have indicated that chromatin-modifying proteins are commonly mutated in human cancers. The lysine-specific methyltransferase 2C (KMT2C/MLL3) is a putative tumor suppressor in several epithelia and in myeloid cells. Here, we show that downregulation of KMT2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. More specifically, cells with low KMT2C activity are deficient in homologous recombination-mediated double-strand break DNA repair. Consequently, these cells suffer from substantially higher endogenous DNA damage and genomic instability. Finally, these cells seem to rely heavily on PARP1/2 for DNA repair, and treatment with the PARP1/2 inhibitor olaparib leads to synthetic lethality, suggesting that cancer cells with low KMT2C expression are attractive targets for therapies with PARP1/2 inhibitors.

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