Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder

Wenjun Jiang,Nan Jia,Chaowan Guo,Juan Wen,Lingqian Wu,Tomoo Ogi,Huiwen Zhang

doi:10.1016/j.bbadis.2021.166106

Abstract

TOP3A promotes processing of double Holliday junction dissolution and also plays an important role in decatenation and segregation of human mtDNA. Recently, TOP3A mutations have been reported to cause Bloom syndrome-like disorder. However, whether the two function play equal roles in the disease pathogenesis is unclear. We retrospectively studied the disease progression of two siblings with Bloom-like syndrome caused by two novel mutations of TOP3A, p.Q788* and p.D479G. Beside the common clinical manifestations, our patients exhibited liver lipid storage with hepatomegaly. In cellular and molecular biological studies, TOP3A deficiency moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency. These changes were rescued by ectopic expression of either of the wildtype TOP3A or TOP3A-D479G. In contrast, reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G. Considering the different impact of the TOP3A-D479G mutation on the genome stability and mitochondrial metabolism, we propose that the impaired mitochondrial metabolism plays an important role in the pathogenesis of TOP3A-deficient Bloom-like disease.

Highlights

TOP3A is a subunit of the BLM-TOP3A-RMI1/2 complex, which promotes processing of double Holliday junction dissolution and plays an important role in decatenation and segregation of human mitochondrial DNA (mtDNA)
In cellular and molecular biological studies, TOP3A deficiency decreased the cellular protein level of RMI1 and RMI2, and moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency
Reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G

Summary

Introduction

TOP3A is a subunit of the BLM-TOP3A-RMI1/2 complex, which promotes processing of double Holliday junction dissolution and plays an important role in decatenation and segregation of human mtDNA. The BLM helicase, along with RecQ-mediated genome instability proteins (RMI1/2) and topoisomerase III alpha (TOP3A), forms a protein complex (BTR complex) that promotes the dissolution of double Holliday junctions (dHJs) throughout the cell cycle and is crucial for genome stability[6,7,8,9,10,11,12]. 11 individuals with TOP3A deficiency-induced Bloom syndrome-like disorder caused by 8 different TOP3A mutations had been reported. Most TOP3A affected individuals, as well as two RMI2 deficient patients, are reported with increased SCEs. Independent from its nuclear role, TOP3A exists in its mitochondrial form and play important role in mitochondrial DNA (mtDNA) replication, decatenation, and segregation machinery[17, 18]. The pathological mechanism and the treatment options of TOP3A deficiency need to be further elucidated[17, 19]

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Conclusion