# The lncRNA PARylator promotes PARP1 activation and resistance to DNA‑damaging therapy in esophageal squamous cell carcinoma

## TL;DR

A long noncoding RNA called PARylator helps esophageal cancer cells survive DNA-damaging treatments by boosting PARP1 activity, suggesting it could be a new treatment target.

## Contribution

Identifies PARylator as a novel lncRNA promoting DNA repair and treatment resistance in esophageal squamous cell carcinoma.

## Key findings

- PARylator interacts with PARP1 and enhances its activity, improving DNA repair in ESCC cells.
- Reducing PARylator increases DNA damage and sensitizes ESCC cells to DNA-damaging therapies.
- PARylator is upregulated in response to DNA damage, supporting cancer cell survival.

## Abstract

Outcomes for patients with esophageal squamous cell carcinoma (ESCC) remain poor, partly due to treatment resistance, particularly to DNA-damaging therapies. Poly(ADP‑ribose) polymerase 1 (PARP1) plays a critical role in repairing single‑strand DNA breaks (SSBs). Unrepaired SSBs can be converted into double‑strand breaks (DSBs) during DNA replication, potentially leading to cell death. Genomic amplification of the distal portion of chromosome 3q (3q26-q29) is a frequent copy‑number alteration in ESCC, which harbors genes encoding several oncoproteins. However, whether long noncoding RNAs (lncRNAs) from this region contribute to ESCC pathogenesis and treatment resistance remains poorly understood.

In situ hybridization and qPCR were used to assess RNA expression. Protein PARylation was evaluated by immunoprecipitation followed by Western blotting. Cellular phenotypes were quantified using the cell counting kit-8, Annexin V/Propidium iodide staining, and clonogenic assays. DNA damage was monitored by immunofluorescence staining for phosphorylated histone H2AX (γH2AX) and p53-binding protein 1 (53BP1) and by comet assays. RNA-protein interactions were assessed through RNA pulldown coupled with mass spectrometry and RNA immunoprecipitation. Chromatin fractionation and detergent pre-extraction immunofluorescence were conducted to examine PARP1 chromatin association. ESCC growth and responses to treatments were evaluated using xenograft models.

The lncRNA LINC00885, hereafter referred to as PARylator, was the most upregulated lncRNA encoded within the 3q26-q29 amplicon in ESCC. PARylator was predominantly nuclear and interacted with PARP1. Knockdown of PARylator increased γH2AX and 53BP1 foci and comet tail moment, triggered apoptosis, reduced clonogenicity, sensitized ESCC cells to cisplatin and ionizing radiation. In vivo, PARylator knockdown impaired tumor growth and increased cisplatin sensitivity in ESCC xenografts. Mechanistically, PARylator promoted PARP1 recruitment to chromatin and catalytic activation, thereby increasing PARP1 auto-PARylation and enhancing the PARylation of X-ray repair cross-complementing 1 (XRCC1). PARylator was further upregulated in response to DNA damage.

The DNA damage-responsive, 3q26-q29 amplicon-encoded lncRNA PARylator promotes PARP1‑mediated PARylation and SSB repair, thereby limiting DSB accumulation and supporting ESCC cell survival and resistance to DNA-damaging therapies. Targeting PARylator, alone or in combination with DNA-damaging agents, may represent a novel avenue for ESCC treatment.

The online version contains supplementary material available at 10.1186/s40164-025-00739-z.