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Hat Grab: Cells Take Extreme Measures to Rescue Their DNA


There’s a famous scene in an Indiana Jones movie where the hero barely makes it under a closing gate descending on him in an underground tunnel. He rolls under the gate in the nick of time, but his signature fedora comes off. With fractions of a second to spare, he reaches his arm under the gate and snatches the hat.

Something like that happens in the cell. Sometimes, when chromosomes are being winched apart by the spindle into the daughter cells, fragments of DNA break off and become entangled in the spindle’s microtubules. Unless they are rescued and make it into the nuclei of the new cells, disaster could result. The resulting cells will become unstable, resulting in cancer or cell death. Time is of the essence! The cell is following a precisely choreographed screenplay, where thousands of actors must play their roles perfectly at the right time and place. Like the gate descending on Indiana Jones, the cleavage furrow is rapidly constricting the midpoint of the spindle, with those fragments stuck there. Can the cell rescue them in time?

This crisis happens daily in life. Like the city folk above ground, oblivious to Indiana Jones and his frantic brush with death under the streets, we hear and see nothing of the near-catastrophes happening inside our cells. But if it weren’t for the cell’s fast-acting hand, all would be lost. The dramatic true story is told in fascinating news from the University of California, Santa Cruz, under the title, “’Hail Mary’ mechanism can rescue cells with severely damaged chromosomes.” The authors liken what happens to a quarterback’s all-or-nothing long pass in the last seconds of a critical football game. It calls for desperate plays.

William Sullivan calls this a “worst case scenario” for the cell. The potential consequences include cell death or a cancerous cell growing out of control. But Sullivan, a professor of molecular, cell, and developmental biology at UC Santa Cruz, has found that the cell still has one more trick up its sleeve to rescue the broken chromosome.

The latest findings from Sullivan’s lab, published in the June 5 issue of Journal of Cell Biology, reveal new aspects of a remarkable mechanism that carries broken chromosomes through the process of cell division so that they can be repaired and function normally in the daughter cells. [Emphasis added.]

Sullivan’s research team studied a strain of fruit flies that they mutated to increase the incidence of DNA fragmentation. By inserting fluorescent tags, they were able to witness “this amazing mechanism, like a Hail Mary pass with time running out.” What they saw was not unlike Indiana Jones’s arm reaching for his hat.

The mechanism involves the creation of a DNA tether which acts as a lifeline to keep the broken fragment connected to the chromosome….

Sullivan’s research has shown that chromosome fragments don’t segregate with the rest of the chromosomes, but get pulled in later just before the newly forming nuclear membrane closes. “The DNA tether seems to keep the nuclear envelope from closing, and then the chromosome fragment just glides right in at the last moment,” Sullivan said.

It’s a good thing this tether works most of the time. When it doesn’t, the action-adventure movie turns into a horror flick.

If this mechanism fails, however, and the chromosome fragment gets left outside the nucleus, the consequences are dire. The fragment forms a “micronucleus” with its own membrane and becomes prone to extensive rearrangements of its genetic material, which can then be reincorporated into chromosomes during the next cell division. Micronuclei and genetic rearrangements are commonly seen in cancer cells.

Think about what is required for this trick to work. Genes have to construct the tether, and enzymes have to know where to attach it. This means that all the information to pull off this whole stunt has to be written into the script before the director calls, “Action!” Could evolution write a script like that? In the neo-Darwinist version, cells that did not have the tether would die or grow cancerous. The cost of selection would be enormous. All the players and their props would have to learn their roles by chance, figuring out by sheer dumb luck where to be and what to do before a cell could succeed at this stunt and survive. We don’t think Sullivan or his funding agencies are relying on chance to pull that off.

We want to understand the mechanism that keeps that from happening,” Sullivan said. “We are currently identifying the genes responsible for generating the DNA tether, which could be promising novel targets for the next generation of cancer therapies.”

Sullivan has just received a new four-year, $1.5 million grant from the National Institute of General Medical Sciences to continue this research.

The “Hail Mary pass” is just one of a whole catalog of strategies the cell can draw on to protect its genome. Here’s another strategy announced at Rice University, where researchers determined that “Biology’s need for speed tolerates a few mistakes.”

Biology must be in a hurry. In balancing speed and accuracy to duplicate DNA, produce proteins and carry out other processes, evolution has apparently determined that speed is of higher priority, according to Rice University researchers.

Rice scientists are challenging assumptions that perfectly accurate transcription and translation are critical to the success of biological systems. It turns out a few mistakes here and there aren’t critical as long as the great majority of the biopolymers produced are correct.

Although the researchers are evolutionists, we can see that what they really found is optimization at work (a form of intelligent design in action).

A new paper shows how nature has optimized two processes, DNA replication and protein translation, that are fundamental to life. By simultaneously analyzing the balance between speed and accuracy, the Rice team determined that naturally selected reaction rates optimize for speed “as long as the error level is tolerable.”

When you think about what a cell has to do before it divides, there’s not much room for evolution in the mistakes. Millions of base pairs must be duplicated in a time crunch, while the molecular machinery is in operation. It’s like duplicating a factory while the machinery is running! A smart manager will recognize that the cost of being too precise is not worth the delay if the results are adequate to meet the requirements. They use an analogy we are familiar with:

Kinetic proofreading is the biochemical process that allows enzymes, such as those responsible for protein and DNA production, to achieve better accuracy between chemically similar substrates. Sequences are compared to templates at multiple steps and are either approved or discarded, but each step requires time and energy resources and as a result various tradeoffs occur.

Additional checking processes slow down the system and consume extra energy,” Banerjee said. “Think of an airport security system that checks passengers. Higher security (accuracy) means a need for more personnel (energy), with longer waiting times for passengers (less speed).”

Despite the one evolution reference, these researchers smell design:

“That makes just as much sense for biology as it does for engineering,” Igoshin said. “Once you’re accurate enough, you stop optimizing.”

We see a similar optimization strategy in news from Brandeis University about double-stranded break (DSB) repair. When one strand of DNA breaks, that’s bad. When both strands of DNA become separated, that’s really bad. Specialized enzymes can inspect and repair these DSBs, but they also have to sacrifice accuracy for speed. The enzymes look for similar sequences to use as a template for the “bandage” that will re-join the strands.

But how perfect does the match have to be? Ranjith Anand, the first author on the Nature paper, said this was one of the central questions that the Haber lab wanted to answer.

They found that repair was still possible when every sixth base in a stretch of about 100 bases was different. Previous studies of RAD51 in the test tube had suggested that the protein had a much more stringent requirement for matching.

That one of the six base pairs could be a mismatch surprised the scientists. The process “is permissive of mismatches during the repairing,” says Anand….

We begin to see a kind of molecular triage going on, as if battlefield medics use whatever is on hand to keep the soldier from dying. “Most damage gets accurately repaired, so the cell is unaffected,” the article says. For somatic cells, imperfect bandages will probably cause no significant harm. Darwinism would require that the mistakes (1) become incorporated into the germline, and (2) provide functional innovations that are positively selected. And thus a wolf became a whale, and a dinosaur took flight into the skies.

Sensible viewers of these action adventures undoubtedly sense good directing, acting, and optimization behind them. Clifford Tabin expressed his amazement about life’s development in back in 2013.

When I teach medical students, they’re more interested in the rare people who are born with birth defects, They want to understand embryology so they understand how things go awry, but I’m more interested in the fact that for everyone sitting in my classroom—all 200 of those medical students and dental students — it went right! And every one of them has a heart on the left side and every one of them has two kidneys, and how the heck do you do that?

You are not just a ball of cells, he says; you are the result of mechanical principles that guide the growth of structures through many stages, subject to physical forces, that usually work. And that is indeed astonishing.

Photo: Hat from Indiana Jones movie, for sale at auction, by Deidre Willard (Indy’s hat) [CC BY 2.0], via Wikimedia Commons.