Abstract
Mammalian haploid somatic cells are unstable and prone to diploidize, but the cause of haploid instability remains largely unknown. Previously, we found that mammalian haploid somatic cells suffer chronic centrosome loss stemming from the uncoupling of DNA replication and centrosome duplication cycles. However, the lack of methodology to restore the coupling between DNA replication and centrosome duplication has precluded us from investigating the potential contribution of the haploidy-linked centrosome loss to haploid instability. In this study, we developed an experimental method that allows the re-coupling of DNA and centrosome cycles through the chronic extension of the G1/S phase without compromising cell proliferation using thymidine treatment/release cycles. Chronic extension of G1/S restored normal mitotic centrosome number and mitotic control, substantially improving the stability of the haploid state in HAP1 cells. Stabilization of the haploid state was compromised when cdk2 was inhibited during the extended G1/S, or when early G1 was chronically extended instead of G1/S, showing that the coupling of DNA and centrosome cycles rather than a general extension of the cell cycle is required for haploid stability. Our data indicate the chronic centriole loss arising from the uncoupling of centrosome and DNA cycles as a direct cause of genome instability in haploid somatic cells, and also demonstrate the feasibility of modulation of haploid stability through artificial coordination between DNA and centrosome cycles in mammalian somatic cells.
Highlights
In animal organisms, haploid or near-haploid somatic cells arise from pathological processes such as parthenogenesis or aberrant chromosome loss in tumorigenesis (Wutz, 2014)
We addressed whether the uncoupling of DNA and centrosome cycles in haploid cells is a primary cause of haploid stability in mammalian somatic cells
We reasoned that if the uncoupling of DNA replication and centrosome duplication cycles is a primary cause of mitotic defects and genome instability in haploid HAP1 cells, these haploidy-linked defects would be circumvented by artificial recoupling of DNA and centrosome cycles
Summary
Haploid or near-haploid somatic cells arise from pathological processes such as parthenogenesis or aberrant chromosome loss in tumorigenesis (Wutz, 2014). Several recent studies have found that haploid mammalian somatic cells commonly suffer severe mitotic delay and/or cell division failure, which potentially makes an important contribution to the progression of diploidization (Guo et al, 2017; He et al, 2017; Olbrich et al, 2017; Yaguchi et al, 2018). These mitotic defects are not seen or much less in their diploidized counterparts, haploidy-specific. The basis of these haploidy-specific defects remains obscure
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