Research Note: When DNA–Protein Crosslinks Overwhelm Repair
Short analyses of recent papers relevant to aging biology
In a previous discussion of age-related protein damage, I used extracellular matrix (ECM) alterations as an example of processes that biology is poorly equipped to reverse. Some forms of molecular deterioration persist because there is little or no dedicated repair machinery for them. Others persist because existing mechanisms lack the capacity to fully reverse the damage within physiological timeframes once it occurs
A recent paper on Ruijs–Aalfs syndrome (RJALS), a rare progeroid disorder caused by defects in the DNA–protein crosslink (DPC) protease SPRTN, shows what happens when a maintenance system does exist, but cannot repair the damage fast enough. (1,2)
Living systems are continually exposed to chemical changes that arise from ordinary chemistry taking place in the warm aqueous environment of the body. Some are derived from metabolism or enzymatic activity, while others would proceed even in nonliving tissue. One such lesion class is DNA–protein crosslinks (DPCs), covalent attachments between proteins and DNA that can form through several routes, including reactive chemistry such as reactions with aldehydes and ROS. These structures physically obstruct replication and transcription and must be removed to maintain genome function. (2)
Under normal conditions, cells initiate repair of DPCs using a specialized protease called SPRTN. The study reports that when SPRTN activity is impaired, DPCs are not efficiently cleared, including during mitosis. Their persistence disrupts chromosome segregation, leading to micronuclei and fragments of DNA mislocalized to the cytoplasm. (1)
At this stage the problem is no longer just the presence of molecular damage. Mislocalized DNA activates the cGAS–STING danger-sensing pathway, an innate immune response normally involved in detecting infection or genomic instability. Chronic activation of this pathway appears to mediate much of the downstream pathology, translating persistent DNA lesions into systemic inflammation and degeneration that produces an organism-level phenotype resembling accelerated aging. (1)
This is not evidence that aging is genetically programmed. Instead, it illustrates how stochastic damage and biological programming interact.
Taken together with long-lived ECM modifications such as glycation, racemization, or isomerization (which often lack effective repair pathways altogether), this example highlights two distinct contributors to aging. Some damage accumulates because biology never evolved the means to fully reverse it. Other damage becomes harmful when maintenance systems are overwhelmed or impaired. Aging emerges from both.
References
1. Tomaskovic I, Prieto-Garcia C, Boskovic M, et al. DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality. Science. 2026;391(6784):eadx9445. doi:10.1126/science.adx9445
2. Perry M, Ghosal G. Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease. Front Mol Biosci. 2022;9:916697. Published 2022 Jun 15. doi:10.3389/fmolb.2022.916697
Good article. I read this quote today which made me nod on agreement with your thinking. “Life is not simply the matter from which it’s composed. Instead, every organism is what physicists call an “open thermodynamic system.” The atoms you’re made of today are not the atoms you will be made of a year from now. Energy and matter are constantly flowing through every cell. This means that living systems are not stable collections of atoms like a rock. Instead, they are stable patterns [of changing atoms] that persist through time. “