Most of us are not aware of the high amount of cell death in our body every day. Cells can die in many different ways. One example is a process called programmed cell death. This is normally beneficial to our body. This programmed type of cell death is by a process called apoptosis, which is from a Greek word meaning falling off, such as leaves from a tree in autumn.

Many cells in our body undergo apoptosis as part of a recycling process, including our cells giving rise to hair, fingernails and toenails, skin, and intestinal lining. These normal, programmed cell deaths are necessary for our body to regenerate tissues and organs for us to remain healthy. However, other non-programmed cell deaths are harmful to our health, such as cell deaths in the heart after a heart attack or to the nerve cells after a stroke.

Apoptotic cell death is a very important process that our body needs to carefully control, along with cell birth. However, cells can become immortal by resistance to apoptotic death signals. Why is this dangerous to us? Some cells may have been deliberately targeted for death because they have become too seriously injured. Our bodies are constantly being exposed to dangers from the environment that can damage DNA, our cell’s important genetic component carried on to daughter cells. Some of these environmental damages can be from the sun’s ultraviolet rays, by-products of some of the foods we eat, cigarette smoke, alcohol and many other things. Damaged DNA can become permanently mutated.

We should keep in mind that cellular immortality is not a good thing as it allows a cell with mutated DNA to continue to live and pass on its mutated DNA to its daughter cells. If this mutated DNA causes immortality, this cell can then become a cancer cell which grows and divides into more cancer cells. This is one important reason why there are many cellular proteins that carefully regulate cell death by apoptosis so that cells can die when they are meant to.

One important regulatory protein is cytoplasmic ATR, which can act to block apoptotic cell death. ATR is a protein in both the cytoplasm and nucleus of our cells, but performs different functions in each location. The absence of ATR in any of our cells during embryonic development causes unwanted death of these cells, or if ATR is present but not in sufficient amounts, brain damage can occur as development proceeds.

Our lab has focused extensively on understanding how cytoplasmic ATR normally prevents apoptotic cell death after DNA damage, because this is such an important process that can lead to cell immortality and subsequent cancer. We discovered that for cytoplasmic ATR to act in avoiding cell death it must have a specific chemical group removed from it, called a phosphate.

My research focuses on how we can increase this phosphate on ATR to allow damaged cells to die. We identified the protein that removes phosphate from human cytoplasmic ATR, activating ATR to avoid cell death. This phosphate-removal protein (called PP2A) is actually involved in many other processes taking place in our bodies daily, and, in fact, accounts for about 1 percent of the over 2 million total proteins in our cells. We have discovered that when this phosphate-removal protein is absent, cytoplasmic ATR keeps its phosphate and allows the damaged cell to die. 

Conversely, when this phosphate-removal protein is above normal amounts in the cell, it removes all the phosphate from human cytoplasmic ATR which acts to prevent cell death after DNA damage, causing cell immortality.

There is, however, the other side of the double-edged sword of cell death: for every phosphate that the phosphate-removal protein needs to remove from ATR, a phosphate-addition protein originally put that phosphate there. This is important because, the specific proteins that regulate the addition of phosphate to cytoplasmic ATR also may be useful for developing drugs that can cause prevent cell death. We are very interested in identifying this phosphate-addition protein.

This is because there are conditions when encouraging cells to live longer can be beneficial; for example, in damaged nerve and heart cells.

We are carefully monitoring ongoing clinical trials using inhibitors of the phosphate-removal protein that acts on cytoplasmic ATR. We are interested in how we can use these results to push our pre-clinical studies further in ways that can directly benefit human health and cancer treatments.

Yetunde Makinwa is earning her PhD at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Yetunde is doing her doctoral research in the laboratory of Yue Zou, PhD, in the Department of Cancer Biology. For more information, contact Yetunde.Makinwa@rockets.utoledo.edu or go to utoledo.edu/​med/​grad/​biomedical

First Published January 4, 2021, 5:00 a.m.