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 some cancer drugs are developed.
Funded by the National Institutes of Health and published in Genes & Developmentthe study shows how ATR helps stabilize the cell’s DNA replication machinery during replication stall, preventing chromosome breakage.
Every time a cell divides, it must copy 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 links them back together in the same sequence. Along the way, everyday factors such as sunlight and normal cellular metabolism can damage some of these building blocks. When the replication machinery encounters damaged DNA, the replication process can stop.
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 replication machinery, known as the replisome, in place at the damaged site long enough for another enzyme to step in and copy the damage. Scientists call this rescue process transposition synthesis, or TLS. Without ATR, the replication machinery breaks down and chromosomes can break. Experiments were performed on cultured human and mouse cells.
“ATR action holds the replication machinery in place at the damaged site, so a TLS polymerase can copy the damage while the rest of the machinery remains in place,” said Satya Prakas, senior author of the study. “It’s this coordination that protects the chromosome from breakage – and it’s the chromosome breakage that causes cancer.”
In cells where ATR was disabled, chromosome breaks after a small dose of UV light increased about tenfold. About one in 10 chromosomes showed visible damage. When the ATR was working 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 remained intact. A TLS polymerase entered, copied over the damaged DNA, and then moved on. Without ATR, this coordination failed. The DNA continued to unwind while the replication proteins fell away, leaving large stretches of exposed, single-stranded DNA. A temporary backup system took over, including an enzyme called PrimPol, which had previously been studied mostly 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 the target of anticancer drugs in clinical trials, based on the idea that cancer cells—because they divide faster than healthy cells—are more dependent on the enzyme to survive. The new study suggests that blocking ATR may also pose greater risks to healthy tissue than previously thought.
“In normal human cells, the process for replication after DNA damage is regulated to be nearly error-free and protects chromosomes from instability,” said Satya Prakas. “In cancer cells, the same process is much more sloppy and gets detached from the replisome – which actually increases instability.”
He added that in healthy tissue, blocking ATR would increase chromosome breaks, increase sensitivity to chemotherapies such as cisplatin, and over time increase the risk of new cancers caused by the treatment itself. Effects will likely appear first in tissues that divide more rapidly, including the lining of the gut and bone marrow.
It is gratifying that efforts are being made to design ATR inhibitors that target cancer cells more precisely, said Satya Prakash.
