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DNA Damage as a Cue to Trigger Milk Production

    Written by: Jyoti Madhusoodanan, Ph.D. | Issue # 121 | 2024

    • Mammary glands have many cells with several-fold higher DNA levels and more than one nucleus. 
    • Reducing the number of these cells lowers the expression of genes that encode milk proteins such as casein. 
    • Physiological DNA damage might be crucial to successful lactation. 

    When copying their DNA for a daughter cell, human cells act like good math students, pausing to check their work for errors and correcting mistakes as they go. The moments they pause, known as checkpoints, are critical to avoiding harmful mutations or other errors that might cause a descendant to go astray. But when forced to work faster, cells accumulate mutations with no time to pause or fix them. 

    A pileup of errors would usually cause cells to stop multiplying so damaged DNA doesn’t make its way into new cells. Now, a new study suggests that this damaged DNA can trigger processes essential to milk production in mammary gland cells in mice [1]. 

    Typically, a replicating cell begins by making a copy of its DNA. Then, the nucleus divides into two, and finally, the cell itself multiplies to produce two daughter cells. Decades ago, researchers reported that during lactation, mammary glands often contained cells with double the normal amount of DNA, suggesting the cells had copied their DNA but not then divided it amongst daughter cells. “It’s been known for quite a while,” says Lindsay Hinck, a developmental biologist at the University of Santa Cruz, senior author of the new work. However, Hinck adds, the observation “didn’t seem like the end of the story” to Rut Molinuevo, a postdoctoral researcher who was the first author on the study. 

    In her earlier research, Molinuevo had found that when DNA is damaged, a cell can stop the process of replication after DNA division but before cell division, so the cell ends up with two copies of its genome. If cells pause long enough at this point, they start over again from the beginning rather than resuming where they paused. As a result, some cells might end up with multiple copies of DNA.

    In the new study, Hinck, Molinuevo and their co-authors investigated why so many cells in the mammary gland underwent this process. The researchers began by testing the DNA content of mammary cells from pregnant and lactating mice. They found that about 35 percent of cells had double the DNA content within a single nucleus, and several cells with multiple copies of DNA were both single and double- nucleated, suggesting that these cells had halted at different points in the cell cycle. 

    The researchers then tested whether DNA damage played a part in the formation of these cells. When they treated a mouse mammary cell line with a DNA damaging chemical, they found that the cells – rather than dying from the damage – began to carry multiple copies of DNA and started to differentiate into milk-producing cells. Injecting the disruptive chemical into mouse mammary glands also led to an increase in cells with multiple copies of DNA as well as an increase in the expression of genes that make milk proteins. “We think of DNA damage as scary, but in this case it seems to serve a good purpose,” Hinck said. 

    To understand the cellular drivers of these changes, the researchers homed in on a checkpoint inhibitor protein named CDK1, which typically checks DNA for errors and stops the cell cycle if they’re found. They found that blocking CDK1’s activity in cultured mammary cells led to greater expression of genes for milk proteins.  

    The researchers found that in mouse mammary glands, a protein named Wee1, which is known to block CDK1, increased in early pregnancy, again when cells were increasing their DNA content, and again at the start of lactation. They found that treating an organoid model of the mouse mammary gland with a Wee1 inhibitor led to fewer cells with several-fold higher DNA and a decrease in the expression of genes encoding milk proteins. 

    To confirm Wee1’s role, the team then developed a mouse strain where they could block Wee1 production. When they did so, they found that pups didn’t survive past a few days of birth and had no milk in their stomachs, and mothers only produced half as much milk as a control group of mice with normal Wee1 levels. 

    Repurposing DNA damage to serve as a cue to start milk production might have been a useful evolutionary tactic, Hinck said. “You have to build a milk supply in a very limited amount of time,” she explains, and the necessary speed leads to a compromise in the accuracy of DNA replication. But in a deft evolutionary twist, mammary cells might be able to use the accumulation of cells with too much DNA as a cue to start producing milk. When lactation ceases, it’s possible – although yet to be confirmed – that cells with larger amounts of DNA are targeted for clearance while the progenitor cells can remain unharmed, Hinck explained. 

    Although the results need to be validated further, they could eventually lead to non-hormonal ways to increase milk production in dairy animals, Hinck said.

    References

    1. Molinuevo R, Menendez J, Cadle K, Ariqat N, Choy MK, Lagousis C, Thomas G, Strietzel C, Bubolz JW, Hinck L. Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation. Nature Communications. 2024 Apr 17;15(1):3288.