Uncoordinated centrosome cycle underlies the instability of non-diploid somatic cells in mammals

Abstract

In animals, somatic cells are usually diploid and are unstable when haploid for unknown reasons. In this study, by comparing isogenic human cell lines with different ploidies, we found frequent centrosome loss specifically in the haploid state, which profoundly contributed to haploid instability through subsequent mitotic defects. We also found that the efficiency of centriole licensing and duplication changes proportionally to ploidy level, whereas that of DNA replication stays constant. This caused gradual loss or frequent overduplication of centrioles in haploid and tetraploid cells, respectively. Centriole licensing efficiency seemed to be modulated by astral microtubules, whose development scaled with ploidy level, and artificial enhancement of aster formation in haploid cells restored centriole licensing efficiency to diploid levels. The ploidy-centrosome link was observed in different mammalian cell types. We propose that incompatibility between the centrosome duplication and DNA replication cycles arising from different scaling properties of these bioprocesses upon ploidy changes underlies the instability of non-diploid somatic cells in mammals.

Tetraploidy-associated centrosome overduplication in mouse early embryos

“…Consistent with these ideas, the extra centrosome is observed in majority of tumor cells and cancer cell lines with chromosomal instability [14]. Interestingly, we recently observed that tetraploidized cell lines derived from near haploid or diploid cancer cells showed accelerated centrosome duplication compared to their haploid or diploid counterparts, which led to chronic extra centrosome generation [15]. Based on this observation we proposed that this tetraploidy-driven centrosome overduplication contributes to genome instability in the tetraploid state.…”

“…Based on this observation we proposed that this tetraploidy-driven centrosome overduplication contributes to genome instability in the tetraploid state. However, it remains to be determined whether the tetraploidy-driven centrosome overduplication potentially takes place in non-cancer systems such as early embryos, especially considering the fact that the tetraploidy-linked extra centrosome was not observed in tetraploidized cells derived from a normal immortalized epithelial cell line hTERT-RPE1 cells [15]. It is also unclear whether the extra centrosome arises in tetraploid cells without the initial doubling of centrosome number after tetraploidization solely from the tetraploidy-driven upregulation of centrosome duplication.…”

Uncoupling of DNA replication and centrosome duplication cycles is a primary cause of haploid instability in mammalian somatic cells

“…To keep constant centrosome number over cell cycle generations, the progression of centrosome duplication is tightly coupled with that of DNA replication under control of cyclin E-cdk2 (Hinchcliffe et al, 1999;Lacey et al, 1999;Matsumoto et al, 1999;Meraldi et al, 1999;Fu et al, 2015). Previously, we found that centrosome duplication was drastically delayed in haploid HAP1 cells compared to their isogenic diploid counterparts, whereas the progression of DNA replication was almost equivalent between these ploidy states (Yaguchi et al, 2018). This uncoupling of DNA and centrosome cycles lead to chronic centrosome loss and frequent monopolar spindle formation specifically in haploid cells (Yaguchi et al, 2018), potentially affecting haploid stability.…”

“…Previously, we found that centrosome duplication was drastically delayed in haploid HAP1 cells compared to their isogenic diploid counterparts, whereas the progression of DNA replication was almost equivalent between these ploidy states (Yaguchi et al, 2018). This uncoupling of DNA and centrosome cycles lead to chronic centrosome loss and frequent monopolar spindle formation specifically in haploid cells (Yaguchi et al, 2018), potentially affecting haploid stability. However, lack of experimental tools that enable the restoration of normal centrosome number and/or spindle polarity without compromising long-term cell viability has precluded us from directly testing causality of haploidy-associated centrosome loss for haploid instability (Yaguchi et al, 2018).…”

“…The cause of haploid instability in mammalian somatic cells remains largely elusive. 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 He et al, 2017;Olbrich et al, 2017;Yaguchi et al, 2018). Interestingly, these mitotic defects are not seen or much less in their diploidized counterparts, hence haploidy-specific.…”