A new study found that progeria is caused by inappropriate bonds between proteins and DNA.
Progeria is a genetic condition that involves accelerated aging. Patients develop wrinkled skin, hair loss, and bone and joint stiffness from a very early age. One of the more unusual forms of this already rare condition is Ruijs-Aalfs progeria syndrome (RJALS). Patients with this variant develop liver cancer in addition to their accelerated aging.
Researchers trying to understand how conditions like RJALS begin had a breakthrough roughly 10 years ago when they discovered that mutations in a gene called SprT-Like N-Terminal Domain (SPRTN) caused the condition.1 The SPRTN protein helps maintain the genome’s stability. One way it does this is by removing DNA-protein crosslinks (DPCs). These covalent bonds between genome and protein are bad news for the cell, choking up essential processes linked to DNA replication and transcription. A new study has now shown how unrepaired DPCs ultimately lead to progeria-like symptoms. The research was published in Science.2
Researchers had previously studied SPRTN’s role in clearing out inappropriate bonds between DNA and proteins during DNA replication.3 But Ivan Dikic, a biochemist at the Goethe University Medical School, wanted to explore how the protein functioned at other stages of the cell replication cycle. Using a proteomic assay, he and his team measured which proteins SPRTN interacted with throughout the replication cycle. They found that it partnered closely with mitotic proteins.
To explore how SPRTN deletion might affect DPC levels during this crucial phase of the cell cycle, the team modified SPRTN protein in HeLa cells such that it could be degraded at a time of their choosing. Deleting SPRTN protein during mitosis caused DPCs to form.
This buildup had ripple effects. The researchers observed the cells develop micronuclei, small bodies outside the main nucleus that indicate defective chromosomal migration. The loss of SPRTN also led to mislocalized DNA fragments throughout the cytoplasm. These events increase the risk of cancer, so to remove the DPCs and restore normal mitosis, the affected cells activated an innate immune pathway called GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), or cGAS‐STING. This pathway further ramps up inflammation.
The team then tested whether this effect was also observed in mice lacking the SPRTN protein. These mice had higher levels of DPCs throughout their bodies and had hyperactivated cGAS‐STING levels, which increased cell death and reduced cell proliferation. The researchers suspected that, in trying to eliminate the DPCs, these anti-cancer processes were inadvertently harming the mice’s tissues. These mice also showed all the hallmarks of progeria-accelerated aging, including graying fur and cataracts. Silencing cGAS reduced all of these issues and eliminated spinal and facial abnormalities, suggesting that the immune processes were causing the premature aging.
In their paper, the researchers wrote that their observations of how SPRTN affects mitosis and its link to immune-related aging are entirely new. Still, they remain unsure whether the protein’s action in mitosis or other cell cycle phases is more important for its effects on health. Stopping cGAS also didn’t entirely fix their mice’s symptoms. The authors hope their discoveries may point to a route to treatment for syndromes linked to DNA damage.
