An unchecked anti-cancer gene wreaks havoc on sperm


This mouse’s testes are in a constant battle between bursting at the seams with sperm and total annihilation of his little swimmers. Image via Wikipedia.

Each of us has over 3 billion base pairs of DNA in every one of our cells. And every time a cell divides, there is a risk of making a critical mistake in a few bases that can eventually lead to cancer. That’s why our cells have lots of fail-safes to make sure that we don’t turn into one big tumor by the time we hit puberty. Damaged DNA triggers a response by the gene p53, known as the “guardian of the cell” by some. If p53 decides the damage is too great, it orders the death of the cell, and cancer is averted. But when p53 itself is damaged, this often leads to (or encourages growth of) cancer.

What does this have to do with sex? Research from Haifin Lin’s lab at Yale University has shown that another gene, Pumilio 1, keeps p53 in check in the testes. When Pumilio is deleted in the mouse, p53 goes crazy and starts sending helpless little sperm cells to their deaths, causing fertility defects and shrunken testes. The research was published this week in the journal Current Biology (see link at bottom).

p53: Keeping your sperm numbers just right

Making sperm takes a lot of cell divisions, and each round can introduce new errors that could make the sperm cell basically trash. Besides the possibility of making crappy sperm, males just plain make too many sperm, and some have to be killed off to avoid having way too many. The total number of sperm produced is regulated by p53. But something has to regulate p53, because it is possible to have too much of a good thing. Too much p53 means too many sperm get killed.

Finding a gene that keeps p53 on a leash in the testes is pretty awesome, and you might think that the authors set out wanting to find such a gene. But science is rarely so straightforward and logical. The authors first set out simply to figure out what a gene called Pumilio 1 does in mice. In flies, the equivalent gene (Pumilio) is essential for many steps of both sperm and egg production. In mice, there are two Pumilio genes (1 and 2, oddly enough). Pumilio 2 is not necessary for making sperm, so the question was: what about Pumilio 1?

Pumilio 1: Saving your sperm from overzealous p53

To answer this, the authors deleted Pumilio 1 from the mouse and looked at sperm production and fertility. First, they noticed that Pumilio 1 mutant mice had testes that were 34% smaller than their normal brothers. As you might expect given these tiny testicles, the mutant mice were 41% less fertile than the regular boys.

When they looked closely at the developing sperm cells, the authors found almost 7 times more cells dying by programmed cell death (or apoptosis) than in normal males. What’s causing all this extra apoptosis? Our good friend and genome guardian: p53.

Stem cells (in blue) divide to make another stem cell plus a new sperm precursor (orange). Each primary spermatocyte makes 2 secondary spermatocytes, which in turn each make 2 mature sperm. Pumilio levels are highest in the primary spermatocyte (green) where it keeps p53 in check. Image via Wikipedia.

If sperm can make it past an early stage–the primary spertmatocyte stage–then they’re safe. This is the stage where Pumilio 1 is usually the most active. This means Pumilio 1 isn’t the only thing standing between p53 and total spermicidal chaos, but it is a pretty important one.

Pumilio 1 works by shutting down expression of certain genes. It binds to a sequence in the messenger RNA and stops it being made into a functional protein. Even though p53 runs rampant in Pumilio 1 mutant mice, it doesn’t mean that Pumilio 1 directly attacks p53. What they found was Pumilio targets about 1,500 genes. None of these are p53, but many of them are genes that turn on p53. So, Pumilio 1 normally targets those genes to keep their protein levels low, so that p53 is kept at a reasonable level in the cell.

Given how similar mouse Pumilio 1 is to the fruit fly version, it’s very likely that our version does the same thing. Some men that don’t make enough sperm might have something wrong with their Pumilio function–though using this knowledge to fix the problem would still take years to accomplish.

What about all those other genes that Pumilio 1 targets? Most aren’t involved in p53 pathways at all. The mutant mice showed at least one other defect: they were about 18% smaller than their normal siblings. In addition, Pumilio 1 is found in other tissues besides the testes, though it is highest in the testes. It will be interesting to see what other things this gene does outside of saving sperm.

Reference
Chen, D., Zheng, W., Lin, A., Uyhazi, K., Zhao, H., & Lin, H. (2012). Pumilio 1 Suppresses Multiple Activators of p53 to Safeguard Spermatogenesis Current Biology DOI: 10.1016/j.cub.2012.01.039

Related article
Secret of sperm quality control revealed by Yale scientists (esciencenews.com)

One thought on “An unchecked anti-cancer gene wreaks havoc on sperm

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