The Roles of RNA Helicases in DNA Damage Repair and Tumorigenesis Reveal Precision Therapeutic Strategies

Abstract

DEAD-box RNA helicases belong to a large group of RNA-processing factors and play vital roles unwinding RNA helices and in ribosomal RNA biogenesis. Emerging evidence indicates that RNA helicases are associated with genome stability, yet the mechanisms behind this association remain poorly understood. In this study, we performed a comprehensive analysis of RNA helicases using multiplatform proteogenomic databases. More than 50% (28/49) of detected RNA helicases were highly expressed in multiple tumor tissues, and more than 60% (17/28) of tumor-associated members were directly involved in DNA damage repair (DDR). Analysis of repair dynamics revealed that these RNA helicases are engaged in an extensively broad range of DDR pathways. Among these factors is DDX21, which was prominently upregulated in colorectal cancer. The high expression of DDX21 gave rise to frequent chromosome exchange and increased genome fragmentation. Mechanistically, aberrantly high expression of DDX21 triggered inappropriate repair processes by delaying homologous recombination repair and increasing replication stress, leading to genome instability and tumorigenesis. Treatment with distinct chemotherapeutic drugs caused higher lethality to cancer cells with genome fragility induced by DDX21, providing a perspective for treatment of tumors with high DDX21 expression. This study revealed the role of RNA helicases in DNA damage and their associations with cancer, which could expand therapeutic strategies and improve precision treatments for cancer patients with high expression of RNA helicases. Significance: The involvement of the majority of tumor-associated RNA helicases in the DNA damage repair process suggests a new mechanism of tumorigenesis and offers potential alternative therapeutic strategies for cancer.

The Association of R-Loop Binding Proteins Subtypes with CIN Implicates Therapeutic Strategies in Colorectal Cancer

“…This was further validated in the drug sensitivity analysis, as demonstrated by the high percentage of negative correlation of RLBP expression with IC50 values of drugs involved in genome stability ( Figure 6 ). The concept is consistent with our previous findings showing that high expression of RNA helicases, DDX21, renders sensitivity for irinotecan, oxaliplatin, and etoposide [ 59 ]. Thus, overall high therapeutic sensitivity in patients would be expected along with better outcomes in CI.…”

“…Moreover, DDX21, which is a significant RLBPs member, was revealed to engage in the HR pathway directly. The high expression of DDX21 leads to excessive sister chromatid exchanges [ 59 ]. PARP1 is required for chromosomal translocations; it displaces the Ku complex and initiates an alternative NHEJ pathway [ 60 ].…”

Pan-cancer analysis reveals DDX21 as a potential biomarker for the prognosis of multiple tumor types

“…DDX21 can effectively unwind R-loops (three-stranded coding RNA (lncRNA) HCP5 can limit the proliferation, migration, and invasion of gastric cancer cells by regulating the expression of DDX21 (40). Another study confirmed DDX21 as a prognostic marker for early colorectal cancer with microsatellite instability (41), which might be a new precision treatment strategy (42). Nevertheless, the role of DDX21 in different tumor types has not been thoroughly investigated.…”

LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization

“…DDX21 acts as a sensor of nucleotide stress and contributes to melanoma development [ 31 ]. Furthermore, DDX21 plays its oncogenic role in colorectal cancer via inducing genome fragility, damaging double-strand repair and procrastinating HR repair [ 33 ]. In line with these findings, we also found that the high expression of DDX21 in gastric cancer leads to poor prognosis and disease progression of gastric cancer patients.…”