Blocking a protective response with PARP inhibitors lets DNA damage pile up at specific spots near the centers of chromosomes, compromising cancer cells’ survival, according to a new study from NYU Langone Health’s Perlmutter Cancer Center published in Nature Cell Biology.
Even partial loss of ESCO2 increased sensitivity in colorectal, ovarian, and lung cancer cells, the researchers found.
ESCO2 Loss Concentrates Damage at Pericentromeric Regions
To find out why ESCO2-depleted cells were sensitive, the researchers used quantitative single-molecule imaging, an ultrasensitive microscopy approach developed in Rothenberg’s laboratory that can distinguish subtypes of replication-associated damage sites other methods cannot readily separate.
“The imaging enabled us to move beyond measuring damage across an entire cell,” Gupta said.
That response depended on PARP1 activity and involved two other proteins: TIMELESS, which helps protect DNA replication, and DDX11, an enzyme that can unwind G-quadruplex structures. When PARP was inhibited in ESCO2-depleted cells, G-quadruplexes built up further, DNA synthesis declined, and damage increased near centromeres.
Location Matters More Than Quantity of DNA Damage
The ESCO2-depleted cells retained a working homologous recombination response—the DNA repair pathway that is impaired in BRCA-mutated cancers for which PARP inhibitors are typically used. This means the sensitivity the researchers observed works through a different mechanism than the one that makes BRCA-mutated tumors respond to these drugs.
The findings point instead to location as a factor in treatment response.
Imaging Patient Cells Could Predict Treatment Response
Rothenberg is working with clinicians to apply the imaging approaches to patient-derived cancer cells, with the goal of identifying patterns of replication stress and DNA damage that could help predict who responds to treatment.
Whether the findings hold in other genetic contexts and with other treatments remains to be tested.
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