ReviewThe mortal strand hypothesis: Non-random chromosome inheritance and the biased segregation of damaged DNA
Introduction
In 1975, John Cairns proposed that “stem cells would be protected against errors of duplication if it were so arranged that the immortal daughter cell always receives the DNA molecules which have the older of the two parental strands and the mortal daughter always collects the molecules with the younger parental strand” [1]. Since then, Cairns’ “immortal strand” hypothesis has been studied in various organisms and cell types. Despite evidence in support of the hypothesis [2], it has met with well-reasoned skepticism arising from observations that fail to support Cairns and from a near-absence of mechanistic insight into the phenomenon [3]. Here, using evidence gained from nearly forty years of study, we put forth a new theory of non-random chromosome segregation and we propose a model as to how it might occur. The main goals are to help guide the evaluation of existing studies of non-random chromosome segregation and to provide testable models for future investigation.
We hypothesize that the segregation of sister chromatids according to relative template strand age is a consequence of replication stress, which is defined as “inefficient DNA replication that causes DNA replication forks to progress slowly or stall” [4]. In our model (Fig. 1), replication stress generates frank DNA damage, asymmetrically, in chromosomes bearing newer template DNA (the “mortal” strands). This creates a situation in which it is advantageous to preferentially segregate chromosomes bearing newer template strands, in which there is DNA damage, to a single daughter cell. We further hypothesize that the preferential segregation is possible because DNA damage repair machinery recruited to sites of replication-derived damage signals to the mitotic spindle apparatus to direct the attachment of spindle microtubules. Recent advances in cell biology give us a framework for understanding how this might occur (see below). The preferential search-and-capture of sister chromatids may happen in concert with asymmetric centrosome behavior at the spindle pole, possibly related to the relative age of the mother centrioles. This centrosome asymmetry could thus direct the co-segregation of damaged chromosomes with fate determinants, such as the protein Numb, that direct the differentiation or cell-cycle exit of the daughter cell inheriting damaged chromosomes. Alternatively, the DNA damage inherited by one of the two daughter cells may by itself instruct the cell to adopt a particular fate. We predict that cells inheriting chromosomes bearing a large burden of DNA damage are prevented from replicating, at least until they are fully repaired. In our model, these daughters may differentiate, senesce, or die.
Section snippets
The origin of DNA damage asymmetry on sister chromatids
Our model identifies replication stress as a source of DNA damage that could give rise to frank DNA breaks that are asymmetrically localized between sister chromatids in a manner that is dependent on the relative age of the template strands. Replication stress encompasses defects in DNA synthesis associated with fluctuations in the availability of dNTPs or other factors required for DNA replication, increased or decreased firing of replication origins (hyper- or hypo-replication, respectively),
Non-random chromosome segregation as a quality control mechanism
In our model of non-random chromosome segregation, conditions that lead to inefficient DNA replication generate DNA damage in chromosomes with newer template strands. In a more traditional view of cell biology, this damage would be expected to initiate a signaling cascade that inhibits cell-cycle progression or even lead to the death of the cell. An alternative outcome, which would enable the preservation of the cell lineage, is the preferential segregation of the entire complement of sister
Conclusion
Non-random chromosome segregation is a phenomenon that has fascinated cell biologists since it was first observed. Much of this fascination stems from the mysteries that surround it, namely, how it occurs and what role it plays. Solving these mysteries has proven difficult, at least in part, because we lack even a framework for understanding how a cell might recognize and partition chromosomes according to the relative age of template DNA strands. Although testable models like the one presented
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2018, Seminars in Cell and Developmental BiologyCitation Excerpt :In other words, the relatively “old” nuclei are positioned near the hyphal tip [130]. The non-random distribution of the labels is consistent with an intriguing phenomenon of non-random segregation of sister chromatids during mitosis, which is thought to happen during nuclear division of some stem cells for preventing the stem cell genomes from acquiring mutations [130–133]. In A. nidulans, it is unknown whether the “old” nuclei would be the ones that enter the process of asexual spore development, and this would be an interesting topic for future studies.
Creating Age Asymmetry: Consequences of Inheriting Damaged Goods in Mammalian Cells
2017, Trends in Cell BiologyCitation Excerpt :In this context, the modified hypothesis of non-random sister chromatid segregation that was recently proposed is intriguing because this suggests that non-random segregation of DNA strands is associated with DNA replication stress [33]. Slowed or stalled replication forks cause DNA damage during replication in the newer strand, and segregation of that newly acquired DNA damage to the non-stem cell daughter may ensure genomic stability of the long-lived stem cell daughter [33]. Thus, the modified immortal strand hypothesis proposes a context-dependent mechanism for when and why sister chromatids segregate non-randomly.
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