Importin KPNA2, NBS1, DNA Repair and Tumorigenesis

Abstract

During the past 20 years, the MRE11-RAD50-NBS1 complex has become an increasingly important focus in basic and clinical cancer research. One main conceptual step forward was made with the discovery of NBS1 and the understanding of its critical pathophysiological role in Nijmegen breakage syndrome. Major efforts were carried out to define the role in DNA repair of this complex. Recently, basic research has continuously extended our understanding of the complexity of the NBS1 complex. MRE11-RAD50-NBS1 complex can no longer be viewed as having a single role in DNA damage repair since it also serves as a sensor and a mediator in cell cycle checkpoint signaling. Meanwhile, studies have challenged the concept that NBS1 only functions as a tumor suppressor in preserving genome integrity in the nucleus. It may also provide an oncogenic role in the cytoplasm which is associated with the PI3-kinase/AKT-activation pathway. Consistent with this aspect, a growing body of clinical evidence suggests that NBS1 contains a deleterious character that depends on its subcellular localization. This review focuses on recent experimental evidences demonstrating how NBS1 is translocated into the nucleus by an importin KPNA2 which mediates NBS1 subcellular localization and the functions of the NBS1 complex in tumorigenesis.

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

“…; refs. 18,20,23,24,26). We initially observed that untreated patients with NSCLC prior to radiotherapy had low numbers of RAD50 foci with a significant rise in RAD50 foci directly in parallel with the induction of radiotherapy.…”

“…Because RAD50 foci formation in tissue biopsies has been shown to be positively correlated with survival (18,20,24,26), we assessed its prognostic value in circulating cells (Fig. 6).…”

“…Following double-stranded breaks in DNA, the RAD50/NBS/MRE11 complex rapidly translocates to the sites of the breakage, forming aggregated nuclear foci until the break is repaired, for example, IRIF (18,20,23,25). Thus, RAD50 can be used as a specific identifier of cells that have been exposed to high levels of radiation, acting as a biological tag of cells from patients that have been directly exposed to radiation targeted to a tumor mass (18)(19)(20)(21)(22)(23)(24)(26)(27)(28).…”

KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

“…In the nucleus, NBS1 acts as tumor suppressor involved in DNA DSB repair, maintaining genome stability. In the cytoplasm, however, NBS1 provides an oncogenic role, which promotes tumorigenesis through binding and activation of the phosphatidylinositol 3-kinase/AKT pathway (22).…”

High nuclear karyopherin α 2 expression is a strong and independent predictor of biochemical recurrence in prostate cancer patients treated by radical prostatectomy

“…2 Karyopherin a 2 (KPNA2) belongs to the karyopherin family and has been described to have an oncogenic role through the modulation of the subcellular localization of cargo proteins relevant for cancer. 3 KPNA2 is also suspected to be involved in cellular proliferation, differentiation, cell-matrix adhesion, colony formation and migration. [4][5][6][7] Increased KPNA2 expression levels, as compared with normal tissue, have been described in various malignancies including breast cancer, 8 melanoma, 9 ovarian cancer 10 and astrocytoma.…”