ATR Enzyme Prevents Chromosome Breaks During DNA Replication

UTMB study reveals critical role of ATR in stabilizing DNA-copying machinery, with implications for cancer therapy.

Without ATR, chromosome breaks after UV exposure increased approximately tenfold—from ~1 in 100 chromosomes to ~1 in 10.

Key Discovery

Researchers at the University of Texas Medical Branch (UTMB) have identified that the enzyme ATR prevents chromosome breaks by stabilizing the replisome—the DNA-copying machinery—at damaged DNA sites during replication. The study, funded by the National Institutes of Health and published in Genes & Development, shows that ATR holds the replisome in place long enough for translesion synthesis (TLS) polymerases to copy past the damage.

How It Works

In normal cells, ATR coordinates the replisome to remain at stalled replication sites, allowing TLS polymerases to bypass DNA damage with relatively high accuracy.
When ATR is absent, the replisome dissociates, exposing single-stranded DNA. A backup enzyme called PrimPol can partially compensate, but this mechanism was previously studied mainly in cancer cells.

Implications for Cancer Therapy

ATR inhibitors are currently in clinical trials, based on the premise that rapidly dividing cancer cells rely more heavily on this enzyme. However, the new findings raise important cautions:

Blocking ATR in normal cells increases chromosome breaks, which may heighten sensitivity to chemotherapies such as cisplatin.
This could potentially raise the risk of treatment-related cancers in patients receiving ATR-inhibitor combinations.

The study's senior author, Satya Prakash, noted a key distinction: normal cells coordinate ATR-dependent TLS with relatively high accuracy, while cancer cells often lack this coordination, leading to genomic instability.

Study Details

Experiments were conducted in cultured human and mouse cells. Researchers tracked protein-level events at stalled replication sites, comparing conditions where ATR was active versus when it was switched off.

Funding and Publication

The study was funded by the National Institutes of Health and published in Genes & Development.