# NYU Langone: ESCO2 loss makes cancer cells sensitive to PARP inhibitors via G4 DNA lesions

- Published: 2026-11-05 20:44 UTC
- Section: Life & Health › Medicine
- Tags: PARP inhibitor sensitivity, ESCO2 loss, G4 DNA structures, replication fork stability, synthetic lethality, pericentromeric regions, single-molecule imaging, NYU Langone Perlmutter Cancer Center
- URL: https://realtech.media/news/rt-0ddd7284f1a9d6d941c7b100_nyu_langone_esco2/

**In cancer cell models, loss of ESCO2 led to G-quadruplex DNA buildup at pericentromeric sites; PARP inhibition blocked the protective response to it.**

![NYU Langone: ESCO2 loss makes cancer cells sensitive to PARP inhibitors via G4 DNA lesions](https://sgzwpqqelzmajkcubgkl.supabase.co/storage/v1/object/public/rt-media/2026/11/cf1df875410f0acb.png)
*nature.com*

Researchers at NYU Langone Health and its Perlmutter Cancer Center report that replication-fork lesions in specific genomic regions determine how sensitive cancer cells are to PARP inhibitors (PARPi). The study was published online on November 5 in Nature Cell Biology and is available on nature.com [1]. The experiments were done in cancer cell models. Eli Rothenberg, professor at NYU Grossman School of Medicine, is a co-corresponding author.

PARPi are used against cancers with defective homologous recombination, but hypersensitivity has also been seen in other genetic contexts. The DNA lesions behind PARPi cytotoxicity remained poorly defined [1].

## ESCO2 loss and G4 lesions

CRISPR screens in breast and small cell lung cancer models identified loss of ESCO2, a replication-coupled cohesin acetyltransferase, as a cause of PARPi hypersensitivity independent of homologous recombination deficiency [1]. Follow-up experiments showed that even partial reduction of ESCO2 increased sensitivity to PARPi in colorectal, ovarian and lung cancer cells.

The team used quantitative single-molecule imaging developed in Rothenberg's laboratory. It showed that ESCO2 loss promotes accumulation of G-quadruplex (G4) DNA structures at a subset of replication-associated sites [1]. These sites were associated with PARP1 activation and with engagement of the fork protection factor TIMELESS, which mitigates G4-induced stress. The G4 lesions localized to fragile pericentromeric regions and engaged the G4 helicase DDX11.

## How PARP inhibition removes the protection

According to the authors, PARP inhibition disrupts this protective G4-processing response by preventing PARP1-dependent engagement of TIMELESS and DDX11. The result is G4 accumulation, DNA damage and chromosomal instability [1]. The authors define the G4–PARP1–TIMELESS–DDX11 axis as a safeguard of replication fork stability at hard-to-replicate loci and describe ESCO2 as a potential therapeutic target for promoting synthetic lethality in PARPi-treated cancers.

Rothenberg noted that DNA damage is usually considered in terms of quantity, whereas this work points to a small subset of sites where replication problems have disproportionately severe consequences. The authors say the location of damage can shape treatment response and may provide a basis for new biomarkers of drug sensitivity. The findings come from laboratory cell models and have not been tested in patients.

## Sources

1. [nature.com](https://www.nature.com/articles/s41556-026-02126-0)
2. [news-medical.net](https://www.news-medical.net/news/20261105/Vulnerable-DNA-sites-make-cancer-cells-sensitive-to-PARP-inhibitors.aspx)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-0ddd7284f1a9d6d941c7b100_nyu_langone_esco2/