Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers

Sep 21, 2026

Uploaded by Hazel

Cancer cells carrying DNA repair defects such as BRCA1/2 mutations are typically vulnerable to PARP inhibitors through synthetic lethality. Emerging clinical observations show PARPi can also suppress tumors regardless of BRCA status, implying additional mechanisms. The study expands prior breast-cancer findings that DDX21 nucleolar localization is PARP1 dependent, linking niraparib treatment to DDX21 mislocalization, reduced rDNA transcription, decreased ribosome biogenesis, and impaired endometrial and ovarian cancer growth. High PARP1 expression and high nucleolar DDX21 correlate with lower niraparib IC50 values and worse patient survival, supporting DDX21 localization as a prognostic biomarker.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Abstract

Mechanism and therapeutic link

Clinical correlations and biomarker potential

Introduction

Ovarian cancer burden and biomarker context

PARP1 inhibitors in standard care

Endometrial cancer needs and trial directions

PARP1 function and rationale for DDX21 targeting

RESEARCH ARTICLE [https://doi.org/10.1158/2767-9764.CRC-24-0001](https://doi.org/10.1158/2767-9764.CRC-24-0001) Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers Marwa W. Aljardali1 , 2 , Kevin M. Kremer1 , 2 , 3 , Jessica E. Parker1 , 2 , 3 , Elaine Fleming3 , Hao Chen4 , Jayanthi S. Lea3 , W. Lee Kraus1 , 2 , and Cristel V. Camacho1 , 2 OPEN ACCESS Check for updates ABSTRACT Cancer cells with DNA repair defects (e.g., BRCA􀀂/􀀃 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA􀀂/􀀃 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target ofPARP1 . We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50 s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. Significance: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi. Introduction Ovarian cancer is the fifth leading factor in women’s cancer-related fatalities (1) . Most patients are diagnosed at an advanced stage with disseminated disease (2, 3) . No less than 15% of patients with high-grade serous ovarian cancer have an inherited predisposition which is predominantly caused by BRCA􀀂/􀀃 mutations (3, 4) . These mutations have served as genetic biomarkers that have led to therapeutic application (5) . Recently, PARP1 inhibitors have garnered 1 Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. 2 Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas. 3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas. 4 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding Author: Cristel V. Camacho, Cecil H. and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235 . E-mail: [cristel.camacho@utsouthwestern.edu](cristel.camacho@utsouthwestern.edu) [doi:](doi: 10.1158/2767-9764.CRC-24-0001)[ 10.1158/2767-9764.CRC-24-0001](doi: 10.1158/2767-9764.CRC-24-0001) This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4 .0) license. © 2024 The Authors; Published by the American Association for Cancer Research significant attention in the treatment of BRCA􀀂/􀀃 mutant tumors because it was demonstrated that PARP inhibition promotes synthetic lethality in BRCA􀀂/􀀃 mutant c

FAQs

How does DDX21 nucleolar localization relate to PARP inhibitor response?

Niraparib inhibits PARP1-mediated ADP-ribosylation of DDX21, causing DDX21 to mislocalize from the nucleolus to the nucleoplasm. This reduces rDNA transcription and downstream ribosome biogenesis and translation, impairing tumor cell growth and linking nucleolar DDX21 to PARPi sensitivity.

What is the observed relationship between DDX21 nucleolar localization and survival?

In endometrial cancer patient samples, higher DDX21 nucleolar localization is significantly associated with decreased survival, indicating prognostic value beyond BRCA status.

Why are PARP inhibitors considered effective even when BRCA1/2 status is not deficient?

Clinical evidence suggests PARPi can inhibit tumor growth independently of BRCA1/2 status, and the paper provides an alternative mechanism: PARP1-dependent nucleolar localization of DDX21 drives processes that influence transcription, translation, and cancer progression.

Sep 21, 2026

Uploaded by Hazel