How can cancer cells bypass treatment?

In the treatment of cancer, there is often such a situation: some therapies can directly target tumor cells, exert pressure on the DNA of these cells to inhibit or stop the DNA replication process; but sometimes, these tumor cells can continue under pressure Survival and division make the patient develop drug resistance during the treatment process and fail to achieve the expected results

In fact, including drugs, a variety of factors inside and outside the cell can become the pressure of DNA replication, causing the DNA replication process to slow down or stop completely

How do these cells acquire mutations and survive stress? For biologists, this is a long-unsolved puzzle

Recently, a study published in Science revealed the key mechanism

First, let us review the process of DNA replication: the Y-shaped structure (replication fork) formed by the DNA strand melts, forming two new strands, the leading strand along the melting direction and the trailing strand in the opposite direction.

Half a century ago, Japanese biologists Reiji Okazaki and Tsuneko Okazaki put forward a conjecture: The lagging strand can only be synthesized into short fragments, which are then spliced ​​into complete DNA by ligase

When the Okazaki fragment matures, the RNA primer at the 5'end will be "topped" by the newly copied DNA fragment, temporarily extending a structure called "5' flap"

However, if the FEN1 gene is missing and the 5'flap cannot be removed in time, these fragments will accumulate and prevent the connection of Okazaki fragments

In order to find those mutations that allow cells to survive under pressure, the research team conducted experiments with yeast cells

▲Cultivate yeast cells lacking Rad27 protein at different temperatures (picture source: reference [1])

As a result, the research team performed whole-genome sequencing on the mutant cells.

When the researchers knocked this mutation into yeast cells where the rad27 gene was knocked out, they found that the cell growth rate, mutation rate, and mutation map were similar to those of ordinary yeast cells

So, how did this mutation occur and help cells survive? Subsequently, the research team uncovered this process by means of whole-genome sequencing and other means

Under high temperature and pressure at 37°C, certain checkpoint kinases in the cell are activated, and they promote the conversion of the remaining 5'flap in the DNA into a more active 3'flap

▲The formation principle of three types of atypical repetitive sequence mutations (picture source: reference [1])

In this way, these cells survived at the cost of mutations

▲The research puts forward a new model of mature error-prone processing of Okazaki fragments (picture source: reference [1])

Note: The original text has been deleted

Reference materials:

[1] Haitao Sun et al.