10
$\begingroup$

Let's assume that a cell fails to replicate its DNA during the S Phase of the cell cycle. Let's also assume that the appropriate CDKs are inactive (perhaps due to mutation or lack of cyclin proteins etc.) and the G2-M checkpoint fails.

2 questions:

  1. Will the Spindle Checkpoint fail due to not having duplicated DNA, or can mitosis complete and form aneuploid daughter cells?

  2. More to the point, if mitosis can complete after a cell fails to replicate its DNA (irrespective of the answer to question 1), can the resulting cell (if viable) lead to a neoplasm or cancer?

My thought is no because the odds of having subsequent generations of cells experience similar losses of DNA via mitosis of un-replicated cells would eventually lead to mostly non-viable next-generation cells and the "uncontrolled" division would cease.

  • Though, admittedly, this assumption is dependent on the assumption that the original cell has a heritable issue that "disables" the appropriate checkpoints (vs some random fluke event) allowing the uncontrolled cell line to continue duplicating with un-replicated genomes.

  • I'm also not sure how ultrafine anaphase bridges (see Moreno et al. 2016) can be informative for this question.

I found a paper (Deshpande et al. 2005) that discusses cyclins and cdks in development and cancer, but their paper focuses on the transition from G1 to the S phase and stops short of discussing mitosis of un-replicated cells


Note: this might sound like a homework question, but I'M the one writing the assignment! In fact, it's an exam, and I'm trying to cover my bases for the answers I provide for a different cancer-related question to ensure there are not multiple correct answers.

$\endgroup$

1 Answer 1

2
$\begingroup$

Question 1

Will the Spindle Checkpoint fail due to not having duplicated DNA, or can mitosis complete and form aneuploid daughter cells?

Yes it is possible. Meiosis 2 essentially does not involve DNA replication.

Perhaps you are only talking about mitotic divisions. I have found two reports that say that cells can replicate without DNA replication.

  1. Chan et al. (2022) show that zebrafish skin (superficial epithelial) cells can continue to "split" without DNA replication. This process apparently helps in rapid skin expansion.

Using time-lapse imaging, we found that many SECs readily divide on the animal body surface; during a specific developmental window, a single SEC can produce a maximum of four progeny cells over its lifetime on the surface of the animal. Remarkably, EdU assays, DNA staining and hydroxyurea treatment showed that these terminally differentiated skin cells continue splitting despite an absence of DNA replication, causing up to 50% of SECs to exhibit reduced genome size.

  1. A preprint by Ganier et al. (2020; still unpublished) reports a study on a triploid mouse embryonic fibroblast cell line (3T3). They show that some daughter cells can receive 1N copy.

The fraction of unlicensed cells (24%) that divided produced two daughter cells, despite the complete absence of DNA replication. If the unlicensed genomes were equally distributed in the two daughter cells, these cells should have 1C DNA content. In agreement, flow cytometry analyses always highlighted a distinct population of ΔDboxGeminin-expressing cells with 1C DNA content that appeared after the first cell cycle (Figures 1A and 4A)

They say that these cells can also re-enter mitosis.

We removed DOX 24 hours after induction to stop ΔDboxGeminin induction (T1, Figure 4F; control cells shown in Supplementary Figure 9) and transfected these cells with a CDT1-encoding plasmid (or empty vector; control) to counteract the effect of the remaining ΔDboxGeminin. 24h after CDT1 transfection (T2), 15.3% of 1C cells were BrdU-positive (Figure 4F, BrdU 24h, right panels) compared with 4.9% of 1C cells transfected with empty vector.

Question 2

if mitosis can complete after a cell fails to replicate its DNA (irrespective of the answer to question 1), can the resulting cell (if viable) lead to a neoplasm or cancer?

If the "asynthetic fission" occurs naturally in zebrafish, it may not be predominantly neoplastic. I think that a reduced genome would make the cells unable to re-replicate.

However, the 1N 3T3 cells can re-enter mitosis and they may undergo some cancerous transformation. This cell line is non-cancerous but is laboratory-generated/propagated. So we don't know about what happens in vivo. The authors did not check if the 1N cells that have re-entered mitosis, have cancer driver mutations in their genome.

Aneuploidy is indeed associated with cancers. Several cancer cells are aneuploid. Aneuploidy can result due to loss of stringency of cell cycle checkpoints (common in cancer cells). Shih et al. (2023) show that aneuploidy can be a driver of tumorigenesis. Briefly, they show that somatic copy number alterations (SCNA) of entire chromosomal arms, can increase the fitness of cancer cells. These SCNAs include both expansions and deletions, and need not contain any oncogenes or tumor suppressor genes. For example,

Chromosome arm 8p is frequently deleted across cancer types, but canonical tumour suppressors have not been detected on 8p (refs. 16,26). We observed less cell death by caspase activity (P = 0.02) and flow cytometry (P = 0.004) in cells with engineered 8p deletion (Extended Data Fig. 6c,d and Supplementary Fig. 2). Of the three 8p del-pos peaks (Fig. 2d), the smallest peak, in 8p12, contained two protein-coding genes, WRN and NRG1.

This doesn't fully answer your question, I believe. So I end my answer with a few guesses.

It is quite likely that effect of aneuploidies on cancer are context dependent (Ben-David and Amon, 2019). My gross expectation would be that loss of an entire chromosome should reduce cell fitness (loss of several genes). Gene essentiality would depend on cell type. It is possible that if essential genes are translocated from a chromosome to another, then the former can be dispensed. Cancer cells not only have aneuploidies but also frequent chromosomal rearrangements.

If one were to artificially stimulate cell division without replication, and that these cells don't have a perfect asymmetric division (2N, 0N), then aneuploidies can result: asymmetric segregation (xN, [2-x]N) followed by diploidization (common in haploid cell lines). This can result in cancer.

However, it remains to be proven that an aneuploidy can indeed result in cancer.


Perhaps this answer comes too late to be helpful for your assignment.

$\endgroup$

You must log in to answer this question.

Not the answer you're looking for? Browse other questions tagged .