Scientists reveal how our cells conduct emergency repairs for DNA
Two new studies from Johns Hopkins University are providing scientists with an unprecedented view of how human cells repair one of the most dangerous forms of genetic damage: a break that severs both strands of the DNA double helix.
Two groundbreaking studies from Johns Hopkins University offer scientists a detailed look at how human cells repair a particularly hazardous form of genetic damage: a break that cuts through both strands of the DNA double helix. This research, published in Nature Communications back-to-back, reveals how cells access damaged DNA, assemble molecular tools to prepare and reconnect the broken ends, and could contribute to improved cancer treatments and gene-editing techniques.
The primary focus is on a repair process called non-homologous end joining, or NHEJ, which is one of the main ways human cells handle emergency damage to their DNA. DNA carries the instructions cells need to function, so a double-strand break is highly dangerous. If not repaired correctly, cells can die or develop mutations that contribute to diseases such as cancer.
Unlike other DNA damage, repairing a double-strand break is more challenging because the broken ends cannot be stitched together easily. In the first study, researchers used cryogenic electron microscopy (cryo-EM) to view DNA in its natural cellular environment—wrapped around histones (protein spools) and with broken ends that are difficult to repair.
Ku70/80 and DNA-PKcs are among the first proteins to arrive at a double-strand break. While Ku70/80 grips the broken DNA, DNA-PKcs helps organize the repair response. Both proteins require a stretch of accessible DNA to operate, but nucleosomes (protein spools) around the DNA can limit access. The study showed that DNA-PKcs helps repair machinery traverse the nucleosome barrier, allowing repair to begin even when the access to the damaged DNA is limited.
The second study delves into what happens once the broken ends are brought together. DNA breaks often have uneven, chemically damaged ends or missing genetic material, requiring additional steps before they can be reconnected. Using cryo-EM, researchers determined how polymerase lambda, a repair protein, attaches to the structure holding the DNA ends together.
Polymerase lambda can add missing DNA building blocks to make the ends compatible for reconnection. The study also identified another protein, PNKP, which prepares chemically damaged DNA ends for reconnection. This indicates that NHEJ can assemble various specialized tools around the same break, creating a multipurpose molecular repair workshop.
These findings have several long-term applications. Radiation therapy and certain chemotherapy drugs create DNA damage that cancer cells cannot survive. Understanding how NHEJ repairs this damage could help researchers develop drugs that make selected cancers more sensitive to radiation or chemotherapy. The research provides detailed molecular blueprints of how cells reach, prepare, and reconnect broken DNA, offering insights into when to enhance or inhibit the repair process.
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