Abstract
Transient site-specific DNA copy-number gains (TSSG) are controlled by histone lysine methylation dynamics.
Major finding: Transient site-specific DNA copy-number gains (TSSG) are controlled by histone lysine methylation dynamics.
Mechanism: Specific KDM5 members regulate the recruitment of distinct KDM4 enzymes to sites that undergo TSSG.
Impact: KDM5 family member depletion may promote the formation of TSSGs during S phase via rereplication.
Cancer cells frequently harbor DNA amplifications, especially in regions that harbor oncogenes and prosurvival genes. Overexpression of the histone 3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A results in transient site-specific copy-number gains (TSSG) that are extrachromosomal and do not cause genome-wide chromosomal instability. However, it is unclear how KDM4A is targeted to sites of copy gain or if additional chromatin factors are involved in TSSG formation. Mishra and colleagues performed an siRNA screen for lysine demethylases (KDM) involved in site-specific copy gains. This screen revealed that KDM5A depletion resulted in increased copy gains on chromosome 1q12h, 1q21, and Xq13.1, whereas other regions were unaffected, demonstrating a role for KDM5A depletion in TSSG formation. The copy gains induced by KDM5A inhibition were transient and were generated during S phase via rereplication. KDM4A was required for KDM5A depletion to promote TSSG formation. Mechanistically, KDM5A loss resulted in increased H3K4me3, which was recognized by KDM4A, thereby recruiting KDM4A to loci that undergo site-specific rereplication and copy gain. KDM4A-independent TSSGs were also identified, these TSSGs required KMT2A and their formation could be blocked by KDM5B overexpression. These findings reveal that H3K4 lysine methyltransferases (KMT) and KDMs are essential for regulation of TSSGs. Similarly, KDM4B reduced H3K36me3 and promoted TSSG formation on chromosome 1p32.3 in a KDM4A-independent manner. Taken together, these findings reveal a network of KMTs and KDMs that regulate site-specific DNA rereplication, providing insight into the mechanisms by which DNA amplifications can occur in normal and cancer cells.
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