KDM4A Lysine Demethylase Induces Site-Specific Copy Gain and Rereplication of Regions Amplified in Tumors

Abstract

SUMMARY Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase and is not stable but regenerated each cell division. Sites with increased copy number are re-replicated and have increased KDM4A, MCM and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, while H3K9/K36 methylation interference promotes gain. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. This begins to establish how copy number changes could originate during tumorigenesis and demonstrates that transient overexpression of specific chromatin modulators could promote these events.

Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements

“…Besides protein-coding genes, somatic changes in regulatory elements located in non-coding genomic regions are also likely contributors to malignancy, as these elements can profoundly influence chromatin structure and gene expression [5][6][7] . Regulatory elements can be altered by epigenetic mechanisms including changes in DNA and histone methylation patterns-in many cancers, these have been associated with methylation-induced transcriptional silencing of tumour suppressor genes 8 , chromosomal instability 9 and loss of imprinting 10 . In GC specifically, several studies have supported a major role for epigenetic alterations in gastric tumorigenesis.…”

The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites

“…Interestingly, various types of human cancer show misregulated expression of KDM4A-D members suggesting that dysregulated expression of KDMs is associated with genomic instability and carcinogenesis (for recent reviews see 97,98 ). The mechanism by which KDM4 dysregulation promotes genomic instability could be related to their emerging functions DNA lesions repair.…”

“…These data altogether suggest that KDM4A catalytic activity provides a potential enzymatic link for generating copy number alterations through replication abnormalities of regions amplified in human tumors. 97 Given the tight correlation between lysine methylation and regulation of gene expression, forthcoming research should address whether KDM proteins exert their functions in preserving genomic integrity by determining the transcription state of the damaged chromatin before and after DNA repair. In addition, future studies are required to identify additional KDM enzymes involved in DDR, map their damage-induced substrates and investigate their role in repairing DNA lesions other than DSBs.…”

Discovering Protein Interactions and Characterizing Protein Function Using HaloTag Technology

“…Advances in mass spectrometry have greatly enabled the ability to undertake these studies, and here we present an additional and significant advancement with the development of HaloTag technology for both efficient capture of protein complexes and functional characterization of human proteins from mammalian cells [8][9][10] . This technology has recently been shown in several studies to be a critical factor for discovery of important interactions, allowing for insight into novel protein function and understanding of disease [11][12][13] . The HaloTag protein fusion was initially developed to address several challenges of traditional affinity tags and antibodies as related to protein capture, purification, and labelling [8][9][10] .…”