John Maciejowski, PhD

John Maciejowski studies how genomic instability shapes cancer. Chromosome mis-segregation, telomere crisis, and breakage-fusion-bridge cycles all leave DNA in the wrong place or the wrong state inside the cell, and his laboratory follows two connected questions from that common origin.

The first concerns the immune consequences of instability. DNA that escapes into the cytoplasm, at micronuclei and at chromosome bridges, is read as a danger signal by the sensor cGAS. His laboratory established that the ER-anchored exonuclease TREX1 degrades this DNA and limits cGAS activation at these sites, identified a protein barrier assembled on ruptured micronuclei that governs access to the exposed DNA, and showed that chromosomally unstable tumors induce TREX1 to shield themselves from immune surveillance. Removing TREX1 restores antitumor immunity in tumors able to mount an interferon response.

The second concerns what instability writes into the cancer genome. His laboratory established APOBEC3A as the dominant source of ongoing APOBEC mutagenesis in human cancer cells and traced its episodic activity to a rare and short-lived cell state. It also studies extrachromosomal DNA, showing that these circular, acentric elements reach daughter nuclei with high fidelity by tethering to mitotic chromosomes through transcription that persists into mitosis.

He completed his PhD at the Gerstner Sloan Kettering Graduate School with Prasad Jallepalli, working on the mechanisms that keep chromosome segregation accurate during mitosis, and his postdoctoral training with Titia de Lange at Rockefeller University, where he found that telomere crisis generates chromothripsis and kataegis. He started his laboratory at Memorial Sloan Kettering in 2017.