RecQL4-Aurora B kinase axis is essential for cellular proliferation, cell cycle progression, and mitotic integrity

Abstract

Human RecQL4 helicase plays critical roles in the maintenance of genomic stability. Mutations in RecQL4 helicase results in three clinically related autosomal recessive disorders: Rothmund–Thomson syndrome (RTS), RAPADILINO, and Baller–Gerold syndrome. In addition to several premature aging features, RTS patients are characterized by aneuploidy involving either loss or gain of a single chromosome. Chromosome mosaicism and isochromosomes involving chromosomes 2, 7, and 8 have been reported in RecQL4-deficient RTS patients, but the precise role of RecQL4 in chromosome segregation/stability remains to be elucidated. Here, we demonstrate that RecQL4 physically and functionally interacts with Aurora B kinase (AURKB) and stabilizes its expression by inhibiting its ubiquitination process. Our study indicates that the N-terminus of RecQL4 interacts with the catalytic domain of AURKB. Strikingly, RecQL4 suppression reduces the expression of AURKB leading to mitotic irregularities and apoptotic cell death. RecQL4 suppression increases the proportion of cells at the G2/M phase followed by an extensive cell death, presumably owing to the accumulation of mitotic irregularities. Both these defects (accumulation of cells at G2/M phase and an improper mitotic exit to sub-G1) are complemented by the ectopic expression of AURKB. Finally, evidence is provided for the requirement of both human telomerase reverse transcriptase and RecQL4 for stable immortalization and longevity of RTS fibroblasts. Collectively, our study suggests that the RecQL4–AURKB axis is essential for cellular proliferation, cell cycle progression, and mitotic stability in human cells.

LMNB2 is a prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

“…These kinases participate in regulating genomic stability, mitosis, and the cell cycle. 21,22 V$E2F1_Q6 and V$E2F1_Q4, the most significant transcription factors that were shown to be associated with LMNB2, belong to the E2F1 family. Numerous studies have reported the promoting effect of E2F1 on multiple cancers, including HCC, and that a high level of E2F1 is correlated with poor HCC survival outcomes.…”

“…The kinases‐target gene set enrichment analysis of the LMNB2 network system revealed that kinase gene sets (kinase_CDK1, kinase_PLK1, kinase_CDK2, kinase_ATM, and kinase_AURKB) were significantly correlated with LMNB2. These kinases participate in regulating genomic stability, mitosis, and the cell cycle 21,22 . V$E2F1_Q6 and V$E2F1_Q4, the most significant transcription factors that were shown to be associated with LMNB2, belong to the E2F1 family.…”

Up-regulated Expression and Related Gene Regulatory Networks of ANLN Predict Poor Prognosis and Correlate with Immune Infiltration in Hepatocellular Carcinoma

“…Moreover, among the highly ANLN-related kinases studied in this study, PLK1, which belongs to the conserved serine/threonine kinases family involved in multiple mitotic processes (including functional maturation of centrosomes and response to DNA damage), is emphasized by previous literature to be a determinant factor of the SN38 sensitivity of tumor cells, and its over-expression is inversely correlated with the survival rate of HCC [14][15][16]. Other kinases, such as CDK1 and AURKB involved in our analysis, also regulate the genomic stability, mitosis and cell cycle [17,18]. In terms of the TFs targeted by ANLN, E2F1 is one of the key links in the cell cycle regulation network, and its aberrant expression is actively involved in HCC genesis and development of HCC, which predicts the unfavorable prognosis for patients [19,20].…”

Increased Expression Together with the Gene Regulation Network of NEIL3 Predicts Poor Prognosis and Correlates with Immune Infiltrates in Hepatocellular Carcinoma

“…Moreover, among the highly NEIL3-related kinases investigated in this study, PLK1, one of the conserved serine/threonine kinase family members involved in multiple mitotic processes (including functional maturation of centrosomes, establishment of the bipolar spindle, chromosome segregation and response to DNA damage), was suggested in previous study to be a factor that determined the SN38 sensitivity of tumor cells, and its over-expression was inversely correlated with the survival rate of HCC [39]. Besides, other kinases, such as CDK1 and AURKB, which are involved in our network, also regulate genomic stability, mitosis and the cell cycle [40,41]. Among the TFs targeted by NEIL3, E2F1 represents a key link in the cell cycle regulation network, and its aberrant expression participates in HCC occurrence and development, which also predicts the unfavorable patient prognosis [42].…”