An unhealed wound leaves a scar. In the genome, an unrepaired DNA lesion leaves a mutation — a permanent edit to the genetic code. Mutations can disrupt gene function, drive disease and aging, but they are also the raw material of genetic diversity that has allowed new traits, and ultimately new species, to emerge. What has remained unclear is why some damaged stretches of DNA get repaired while others do not.
A new study published in Nature Communications, from the laboratory of Ariel Afek at the Weizmann Institute of Science, pinpoints which DNA sequences and structures several major repair enzymes preferentially target—and suggests those preferences have left a lasting signature on the human genome, one that may also factor into how cells turn cancerous.
Every cell absorbs thousands of DNA-damaging chemical reactions daily. “When DNA repair systems work properly, they repair most of the damage, but not all of it,” Afek explains. “Therefore, the rate at which mutations accumulate is a balance between the rate of damage and the rate of repair. This balance varies across different areas of the genome, and we still do not understand why certain mutations manage to accumulate in specific regions. Most studies to date have focused on changes that leave a ‘scar’ – a mutation. But to fully understand these changes, we must also consider the genetic ‘wounds’ themselves, including those that are repaired without leaving a trace.”
To read out where in the genome repair succeeds or fails, Afek’s team built a chip loaded with thousands of short synthetic DNA sequences, each engineered with identical damage but distinct flanking sequence context. Doctoral student Noga Levy, who led the study, says the three repair enzymes tested behaved “like a good editor examining every word in its context”— sensitive to the exact combination of bases surrounding the damage, with bases even five positions away influencing recognition and binding. The preferred sequences shared structural traits; one enzyme favored sequences producing an unusually narrow region of the DNA helix.
To explain that structural preference, the Weizmann group partnered with Brian P. Weiser’s team at Rowan University for a computer simulation, which showed an amino acid on the enzyme scanning nearby sequence and gravitating toward the negative charge typical of narrow helical regions.
The team then asked whether these sequence preferences left a mark on the genome over evolutionary time. DNA’s paired-base structure normally keeps A matched with T and C with G; a common form of damage swaps out a C base, breaking that pairing, and repair enzymes are tasked with catching and correcting it. The researchers found that genomic regions repaired efficiently by one enzyme retained more C bases, while regions it repaired poorly accumulated more unrepaired changes—a correlation matching their prediction. “This finding paves the way for a better understanding of the course of human evolution,” Afek says. “To identify which genomic changes were adopted by humans to survive a changing environment, we must first understand which changes accumulate naturally due to the preferences of the repair mechanisms.”
The same dynamic plays out within a single lifetime, not just across evolutionary time: tumors arise when mutations pile up in one cell until it multiplies uncontrollably. “We found a correlation between the repair enzymes’ preferences and mutational signatures—patterns of mutations—in human tumors,” Levy says. “One possibility is that a process in the bodies of cancer patients damaged the repair enzymes, allowing mutations to pile up in areas that were previously protected. Alternatively, over the course of evolution, the repair enzymes may have adapted to target regions that are inherently more vulnerable. Either way, this reinforces our understanding that repair mechanisms play a key role in how cancer develops.”
A separate project in Afek’s lab, led by graduate student Noga Carmon, is now extending this approach to additional repair mechanisms. “Understanding how repair mechanisms ‘choose’ their targets opens up all kinds of ways to harness them for our own needs,” Afek says. “We already use these enzymes as tools in gene editing. A deeper understanding will allow us to fine-tune these technologies and perhaps even engineer enzymes that provide better genetic protection. Since failures in repair mechanisms are a primary driver of cancer, my hope is that understanding them will pave the way for new, more targeted therapies.”
A new study published in Nature Communications, from the laboratory of Ariel Afek at the Weizmann Institute of Science, pinpoints which DNA sequences and structures several major repair enzymes preferentially target—and suggests those preferences have left a lasting signature on the human genome, one that may also factor into how cells turn cancerous.
Every cell absorbs thousands of DNA-damaging chemical reactions daily. “When DNA repair systems work properly, they repair most of the damage, but not all of it,” Afek explains. “Therefore, the rate at which mutations accumulate is a balance between the rate of damage and the rate of repair. This balance varies across different areas of the genome, and we still do not understand why certain mutations manage to accumulate in specific regions. Most studies to date have focused on changes that leave a ‘scar’ – a mutation. But to fully understand these changes, we must also consider the genetic ‘wounds’ themselves, including those that are repaired without leaving a trace.”
To read out where in the genome repair succeeds or fails, Afek’s team built a chip loaded with thousands of short synthetic DNA sequences, each engineered with identical damage but distinct flanking sequence context. Doctoral student Noga Levy, who led the study, says the three repair enzymes tested behaved “like a good editor examining every word in its context”— sensitive to the exact combination of bases surrounding the damage, with bases even five positions away influencing recognition and binding. The preferred sequences shared structural traits; one enzyme favored sequences producing an unusually narrow region of the DNA helix.
To explain that structural preference, the Weizmann group partnered with Brian P. Weiser’s team at Rowan University for a computer simulation, which showed an amino acid on the enzyme scanning nearby sequence and gravitating toward the negative charge typical of narrow helical regions.
The team then asked whether these sequence preferences left a mark on the genome over evolutionary time. DNA’s paired-base structure normally keeps A matched with T and C with G; a common form of damage swaps out a C base, breaking that pairing, and repair enzymes are tasked with catching and correcting it. The researchers found that genomic regions repaired efficiently by one enzyme retained more C bases, while regions it repaired poorly accumulated more unrepaired changes—a correlation matching their prediction. “This finding paves the way for a better understanding of the course of human evolution,” Afek says. “To identify which genomic changes were adopted by humans to survive a changing environment, we must first understand which changes accumulate naturally due to the preferences of the repair mechanisms.”
The same dynamic plays out within a single lifetime, not just across evolutionary time: tumors arise when mutations pile up in one cell until it multiplies uncontrollably. “We found a correlation between the repair enzymes’ preferences and mutational signatures—patterns of mutations—in human tumors,” Levy says. “One possibility is that a process in the bodies of cancer patients damaged the repair enzymes, allowing mutations to pile up in areas that were previously protected. Alternatively, over the course of evolution, the repair enzymes may have adapted to target regions that are inherently more vulnerable. Either way, this reinforces our understanding that repair mechanisms play a key role in how cancer develops.”
A separate project in Afek’s lab, led by graduate student Noga Carmon, is now extending this approach to additional repair mechanisms. “Understanding how repair mechanisms ‘choose’ their targets opens up all kinds of ways to harness them for our own needs,” Afek says. “We already use these enzymes as tools in gene editing. A deeper understanding will allow us to fine-tune these technologies and perhaps even engineer enzymes that provide better genetic protection. Since failures in repair mechanisms are a primary driver of cancer, my hope is that understanding them will pave the way for new, more targeted therapies.”