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

Hongbo Fang,Dongliang Mo,Yuqi Zhu,Shuchen Yang,Kaifeng Niu,Adayabalam S Balajee,Zixiang Chen,Qunsong Tan,Yueyang Li,Di Wei,Yongliang Zhao

doi:10.1038/s41389-018-0080-4

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.

Highlights

Introduction HumanRecQL4 helicase plays multifaceted roles in the maintenance of genomic stability and mutations in RecQL4 leading to three autosomal recessive disorders: Rothmund–Thomson syndrome (RTS), RAPADILINO syndrome, and Baller–Gerold syndrome (BGS), and these three syndromes are somewhat clinically related[1]
RecQL4 physically interacts with AURKB kinase The inherent chromosomal instability manifested as mosaicism and isochromosomes in RecQL4-deficient RTS patients prompted us to identify some of the downstream targets of RecQL4
When Flag-AURKB was precipitated with anti-Flag antibody, a band corresponding to the native RecQL4 protein (~133 kDa) was detected with antiRecQL4 antibody, demonstrating the physical interaction of AURKB with RecQL4 (Fig. 1a)

Summary

Introduction

RecQL4 helicase plays multifaceted roles in the maintenance of genomic stability and mutations in RecQL4 leading to three autosomal recessive disorders: Rothmund–Thomson syndrome (RTS), RAPADILINO syndrome, and Baller–Gerold syndrome (BGS), and these three syndromes are somewhat clinically related[1]. Fang et al Oncogenesis (2018)7:68 mosaicism is due to chromosome segregation error occurring after zygote formation and initiation of cell division[8]. These defects in RTS patients indicate a pivotal role for RecQL4 in chromosome segregation process. Any disruption in chromosome segregation is likely to result in mitotic catastrophe causing cell death. Cancer cells overcome the mitotic catastrophe by achieving an increased expression for some of the pro-survival proteins including Survivin[10]

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Results

Conclusion