Abstract
Mechanisms of DNA damage and repair signaling are not completely understood that hinder the efficiency of cancer therapy. Urokinase-type plasminogen activator receptor (PLAUR) is highly expressed in most solid cancers and serves as a marker of poor prognosis. We show that PLAUR actively promotes DNA repair in cancer cells. On the contrary, downregulation of PLAUR expression results in delayed DNA repair. We found PLAUR to be essential for activation of Checkpoint kinase 1 (CHK1); maintenance of cell cycle arrest after DNA damage in a TP53-dependent manner; expression, nuclear import and recruitment to DNA-damage foci of RAD51 recombinase, the principal protein involved in the homologous recombination repair pathway. Underlying mechanism implies auto-/paracrine signaling of PLAUR/TLR4 receptor complex leading to activation of CHK1 and DNA repair. The signaling is induced by a danger molecule released by DNA-damaged cells and mediates, at least partially, activation of DNA-damage response. This study describes a new mechanism of DNA repair activation initiated by auto-/paracrine signaling of membrane receptors PLAUR/TLR4. It adds to the understanding of role of PLAUR in cancer and provides a rationale for therapeutic targeting of PLAUR/TLR4 interaction in TP53-positive cancers.
Highlights
Therapeutic efficiency of many cancer chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage
PLAUR increases the efficiency of DNA repair
GFP expression was assessed by FACS, which showed that PLAUR-expressing cells exhibited increased DNA repair efficiency when compared with wild-type (WT) cells and that PLAUR can influence both the homologous recombination repair pathway (HR) and non-homologous end joining (NHEJ) repair pathways (Figure 1a)
Summary
Therapeutic efficiency of many cancer chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage. Detection of DNA damage leads to cell cycle arrest, regulation of DNA replication and activation of the repair pathway. In response to DNA damage, CHK1 is phosphorylated at Ser[345] primarily by ATR kinase,[2] to arrest the cell cycle in S and at G2/M phases that promote DNA repair before cell division. CHK1 phosphorylates a variety of intracellular substrate proteins including the recombinase RAD51, the central molecule in HR pathway that binds single-strand DNA at the sites of damage-forming filaments that are observed microscopically as nuclear foci. RAD51 overexpression is observed in many cancers and is associated with an increased efficiency of DNA repair and resistance to chemotherapy.[5]. Damaged cells benefit from the feedback rescue signal of bystander counterparts.[7] BE has important therapeutic significance because it can compromise efficiency of irradiation and cause deleterious effects in off-target healthy tissues. Our recent findings revealed a link between PLAUR and DNA damage-induced activation of the ubiquitin-proteasome system,[11] resulting in delayed DNA repair
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