We all know that mutations occurring in the synthesis of our cells lead to cancer, whether that be via ultraviolet light radiation, the inhalation of cigarette smoke over a long period of time, or otherwise. But how do these mutations actually occur, and if modern science knows that much, why can’t scientists step in before the mutation occurs in the cell and stop the creation of a cancerous one altogether? While the answer to this is evidently easier said than done, researchers such as Szymon Barcawz, Rahul Bhomick, Malgorzata Clausen, Marisa Dinis, Masato Kanemaki, Ying Liu, Katrine Lundgaard, and Wei Wu have found a way to limit the success of cancer-yielding cell mutations.
In this study titled, ‘Mitotic DNA Synthesis in Response to Replication Stress Requires Sequential Action of DNA Polymerases Zeta and Delta in Human Cells,’ researchers studied the replication process of cells, also known as mitosis, in human body cells (all human cells except gametes, sex cells). In order to understand the study fully, a few biological concepts should be covered first; For starters, the activation of the oncogene in relation to developing cancer. ‘Oncogene’ is simply a term for a mutated cell which turns cancerous. The activation of such creates disorder to cells going through mitosis called DNA replication stress, the name of which essentially reveals its effect: when genetic material is being synthesized under these conditions, it is extremely difficult for the mitotic cell to correctly replicate, causing faulty, under-replicated DNA regions (UDRs) to be built. Since DNA replication is completed in the S phase of interphase, which technically is before the commencement of mitosis in a cell; enough genetic material needs to be available for the cell to split in order for it to be replicated. Therefore, if UDRs are going to occur in a cell, they are created during this time.
However, our cells have developed clever adaptations to attempt to fight this type of cellular mistake. The strategy includes performing “‘unscheduled’ DNA synthesis in mitosis (termed MiDAS) that serves to rescue under-replicated” genetic material (Barcawz et al.). In studying this cellular defense mechanism, these researchers have discovered how exactly cells make up for a faulty S phase (the phase which copies DNA during mitosis) utilizing DNA gap-filling mechanisms (REV1 and Pol ζ) and DNA polymerases (group of enzymes) whose sole purpose is to replicate unfinished genomes (Pol δ). The study’s main goal, however, was to reveal which of these polymerases was the most crucial in the “rescuing” of under-developed genetic material, which were not, and which were not really necessary at all.
The researchers were most interested in studying POLDI (a subunit of Pol δ), REV 1, and REV 3 / REV 7 (both subunits of Pol ζ). These are all different polymerases whose main job is to “[promote] the bypass of damaged DNA sites” (Barcawz et al.). Each one works to solve a different issue within DNA replication that could lead to a mutation. For example, a TLS polymerase called Pol ζ4 is better at “bypassing bulky regions” of genetic material than the others (Barcawz et al.); this can be defined as Pol ζ4’s ‘role.’
A crucial realization in this study was that the polymerases Pol ζ and Pol δ may actually be switching roles at some point within the rescuing process by switching their subunits, which we defined earlier as POLDI, and REV3 / REV 7. But, this still doesn’t answer the question of whether or not all the aforementioned polymerases are essential in the process of fixing mutations in the copying of genetic material during mitosis.
The study at hand was successful at answering this question. It found that POLDI, REV1, and REV 3 are crucial to MiDAS, while REV7 is not at all. Additionally, it was discovered that POLDI and REV1 colocalize with another substance (FANCD2) in mitosis, which reveals how they both indeed play a role in the ‘rescue’ of under-replicated regions” (Barcawz et al.).
However, something unexpected about REV1 was also discovered. While it was found to be useful in mending UDRs in conjunction with POLDI and FANCD2, it actually does more harm than good: When REV1 was removed from the rescuing process in a situation where all the cell’s defense mechanisms failed at stopping the synthesis of a cancer cell, cancer cells were much less likely to survive in the human body. This suggests that it is very possible for a new and effective way to treat cancer to be the inhibition of the presence of REV1 polymerase.
In the coming years, if the inhibition of REV1 is found to be possible and turns out to be a promising way of preventing cancer cells from surviving in the body, we could be looking at a groundbreaking advancement to modern medicine and the world of cancer treatment as we know it changing forever.
Real image of cancer cell under a microscope.
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