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EMBO Rep. 2019 Mar;20(3). pii: e46821. doi: 10.15252/embr.201846821. Epub 2019 Jan 21.

The lysine-specific methyltransferase KMT2C/MLL3 regulates DNA repair components in cancer.

Author information

1
Biomedical Research Foundation Academy of Athens, Athens, Greece.
2
Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
3
Department of Medical Genetics, Medical School, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
4
University Research Institute for the Study and Treatment of Childhood Genetic and Malignant Diseases, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
5
First Department of Urology, "Laiko" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
6
Laboratory of Health Physics, Radiobiology & Cytogenetics, National Center for Scientific Research (NCSR) "Demokritos", Athens, Greece.
7
Biomedical Research Foundation Academy of Athens, Athens, Greece aklinakis@bioacademy.gr.

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.

KEYWORDS:

DNA repair; KMT2C; PARPi sensitivity; epigenetic regulation

PMID:
30665945
DOI:
10.15252/embr.201846821
Free PMC Article

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