KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors

Joshua C. Black, Amity L. Manning, Capucine Van Rechem, Jaegil Kim, Brendon Ladd, Juok Cho, Cristiana M. Pineda, Nancy Murphy, Danette L. Daniels, Cristina Montagna, Peter W. Lewis, Kimberly Glass, C. David Allis, Nicholas J. Dyson, Gad Getz, Johnathan R. Whetstine

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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 is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, whereas 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.

Original languageEnglish (US)
Pages (from-to)541-555
Number of pages15
JournalCell
Volume154
Issue number3
DOIs
StatePublished - Aug 1 2013

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Chromosomal Instability
Lysine
Chromatin
Tumors
Cells
Methylation
Multicarrier modulation
DNA-Directed DNA Polymerase
Chromosomes
S Phase
Cell Division
Modulators
Neoplasms
Cell Cycle
Carcinogenesis
Enzymes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Black, J. C., Manning, A. L., Van Rechem, C., Kim, J., Ladd, B., Cho, J., ... Whetstine, J. R. (2013). KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell, 154(3), 541-555. https://doi.org/10.1016/j.cell.2013.06.051

KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. / Black, Joshua C.; Manning, Amity L.; Van Rechem, Capucine; Kim, Jaegil; Ladd, Brendon; Cho, Juok; Pineda, Cristiana M.; Murphy, Nancy; Daniels, Danette L.; Montagna, Cristina; Lewis, Peter W.; Glass, Kimberly; Allis, C. David; Dyson, Nicholas J.; Getz, Gad; Whetstine, Johnathan R.

In: Cell, Vol. 154, No. 3, 01.08.2013, p. 541-555.

Research output: Contribution to journalArticle

Black, JC, Manning, AL, Van Rechem, C, Kim, J, Ladd, B, Cho, J, Pineda, CM, Murphy, N, Daniels, DL, Montagna, C, Lewis, PW, Glass, K, Allis, CD, Dyson, NJ, Getz, G & Whetstine, JR 2013, 'KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors', Cell, vol. 154, no. 3, pp. 541-555. https://doi.org/10.1016/j.cell.2013.06.051
Black, Joshua C. ; Manning, Amity L. ; Van Rechem, Capucine ; Kim, Jaegil ; Ladd, Brendon ; Cho, Juok ; Pineda, Cristiana M. ; Murphy, Nancy ; Daniels, Danette L. ; Montagna, Cristina ; Lewis, Peter W. ; Glass, Kimberly ; Allis, C. David ; Dyson, Nicholas J. ; Getz, Gad ; Whetstine, Johnathan R. / KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. In: Cell. 2013 ; Vol. 154, No. 3. pp. 541-555.
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