Heterochromatin, DNA Replication, and Cancer

Dense areas of chromatin, such as in centromeres, telomeres, and other sequences of noncoding DNA, pose a major challenge for DNA replication. Compacted chromatin is thought to inhibit replication initiation and obstruct progression of the replication machinery. Recent analyses of various somatic and cancer cells have revealed that repressive chromatin is associated with regions of high mutation density. Little is known about the molecular mechanisms that control and facilitate DNA replication at these heterochromatic domains, but cancer cells may harness these mechanisms to sustain their proliferative demands. Evidence suggests this is true in ovarian cancers as well as multiple myeloma.

Marcus B. Smolka, Molecular Biology and Genetics, is working to elucidate the mechanisms of proper heterochromatin replication to understand fundamental aspects of genome maintenance and the control of cell proliferation. This project is centered on METTL13 (Methyltransferase-like 13). While METTL13 has been found amplified and overexpressed in cancers, nothing was previously known about its cellular functions. Smolka and his team have uncovered how METTL13 sustains cell proliferation, identifying it as a possible key player in linking the DNA replication machinery to the control of heterochromatin.

Smolka, in collaboration with Amnon Koren, Molecular Biology and Genetics, is now combining cutting-edge proteomic and genomic techniques with biochemical and cell biological approaches to dissect the action of METTL13 and establish its role in controlling chromatin dynamics, DNA replication, and genome integrity. The results may reveal a fundamental mechanism of heterochromatin replication and replication timing control, while establishing novel drug targets for modulating chromatin dynamics and the proliferative capacity of cancer cells. NIH Award Number: 1R01GM123018

Cornell Researchers

Funding Received

$1.2 Million spanning 4 years

Sponsored by

Other Research Sponsored by National Institutes of Health, National Institute of General Medical Sciences