GALVESTON, Texas — Researchers at The University of Texas Medical Branch (UTMB) have identified how a key enzyme called ATR protects DNA from breaking when cells copy damaged genetic material, a discovery that could affect how certain cancer drugs are developed.
Funded by the National Institutes of Health and published in Genes & Development, the study shows how ATR helps stabilize the cell's DNA-copying machinery during replication stalls, preventing chromosomes from breaking.
Each time a cell divides, it must duplicate its DNA, the helix-shaped molecule that makes up chromosomes and carries genetic information. To do this, the cell unzips and copies billions of DNA building blocks, known by the letters A, T, C and G, and then zips them back together in the same order. Along the way, everyday factors such as sunlight and normal cellular metabolism can damage some of those building blocks. When the copying machinery encounters damaged DNA, the replication process can stall.
Jung-Hoon Yoon and Karthi Sellamuthu, working in the laboratories of Satya Prakash, PhD , and Louise Prakash, PhD , found that ATR's role is to hold the DNA-copying machinery, known as the replisome, in place at the damaged site long enough for another enzyme to step in and copy past the damage. Scientists call this rescue process translesion synthesis, or TLS. Without ATR, the replication machinery falls apart and chromosomes can break. The experiments were conducted in cultured human and mouse cells.
"ATR action holds the replication machinery in place at the damaged site, so a TLS polymerase can copy past the lesion while the rest of the machinery stays put," said Satya Prakash, the study's senior author. "That coordination is what protects the chromosome from breaks — and chromosome breaks are what cause cancer."
In cells where ATR was switched off, chromosome breaks after a small dose of ultraviolet light increased roughly tenfold. About one chromosome in 10 showed visible damage. When ATR was functioning normally, the rate was closer to one in 100.
To understand why, the research team tracked what happens at a stalled replication site, protein by protein. When ATR was present, the replication machinery stayed intact. A TLS polymerase moved in, copied past the damaged DNA, and then moved on. Without ATR, that coordination failed. The DNA continued to unzip while the copying proteins dropped away, leaving long stretches of exposed, single-stranded DNA. A temporary backup system took over, including an enzyme called PrimPol, which had previously been studied mainly in cancer cells and was not known to play this role in normal cells.
The findings have important implications for cancer drug development. ATR is already a target of cancer drugs in clinical trials, based on the idea that cancer cells—because they divide more rapidly than healthy cells—depend more heavily on the enzyme to survive. The new study suggests that blocking ATR may also carry greater risks for healthy tissue than previously thought.
"In normal human cells, the process for copying past the DNA damage has been tuned to be almost error-free, and it protects chromosomes from instability," Satya Prakash said. "In cancer cells, the same process is much sloppier and runs detached from the replisome — which actually adds to instability."
He added that in healthy tissue, blocking ATR would increase chromosome breaks, heighten sensitivity to chemotherapies such as cisplatin, and over time raise the risk of new cancers caused by the treatment itself. The effects would likely appear first in tissues that divide most rapidly, including the lining of the gut and bone marrow.
It is gratifying that efforts are underway to design ATR inhibitors that more precisely target cancer cells, Satya Prakash said.
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