Junk DNA Kept in Good Repair by Nuclear Membrane

Heterochromatin has the dubious distinction of being called the “dark matter” of DNA, and it has even suffered the indignity of being dismissed as “junk DNA.” But it seems to get more respectful treatment inside the nucleus, where it has the benefit of a special repair mechanism. This mechanism, discovered by scientists based at the University of Southern California (USC), transports broken heterochromatin sequences from the hurly-burly of the heterochromatin domain so that they can be repaired in the relative peace and quiet of the nuclear periphery.

This finding suggests that the nuclear membrane is more versatile than is generally appreciated. Yes, it serves as a protective container for nuclear material, and it uses its pores to manage the transport of molecules in and out of the nucleus. But it may also play a special role in maintaining the integrity of heterochromatin, which tends to be overlooked because it consists largely of noncoding DNA, including repetitive stretches of no apparent function.

“Scientists are now starting to pay a lot of attention to this mysterious component of the genome,” said Irene E. Chiolo, Ph.D., an assistant professor at USC. “Heterochromatin is not only essential for chromosome maintenance during cell division; it also poses specific threats to genome stability. Heterochromatin is potentially one of the most powerful driving forces for cancer formation, but it is the ‘dark matter’ of the genome. We are just beginning to unravel how repair works here.”

Dr. Chilo led an effort to understand how heterochromatin stays in good repair, even though it is particularly vulnerable to a kind of repair error called ectopic recombination. This kind of error is apt to occur when flaws in repeated sequences undergo homologous recombination (HR) by means of double-strand break (DSB) repair. Specifically, repeated sequences tend to recombine with each other during DNA repair.

Working with the fruit fly Drosophila melanogaster, Dr. Chilo’s team observed that breaks in heterochromatin are repaired after damaged sequences move away from the rest of the chromosome to the inner wall of the nuclear membrane. There, a trio of proteins mends the break in a safe environment, where it cannot accidentally get tangled up with incorrect chromosomes.

The details appeared October 26 in Nature Cell Biology, in an article entitled, “Heterochromatic breaks move to the nuclear periphery to continue recombinational repair.”

“[Heterochromatic] DSBs move to the nuclear periphery to continue HR repair,” the authors wrote. “Relocalization depends on nuclear pores and inner nuclear membrane proteins (INMPs) that anchor repair sites to the nuclear periphery through the Smc5/6-interacting proteins STUbL/RENi. Both the initial block to HR progression inside the heterochromatin domain, and the targeting of repair sites to the nuclear periphery, rely on SUMO and SUMO E3 ligases.”

“We knew that nuclear membrane dysfunctions are common in cancer cells,” Dr. Chiolo said. “Our studies now suggest how these dysfunctions can affect heterochromatin repair and have a causative role in cancer progression.”

This study may help reveal how and why organisms become more predisposed to cancer as they age—the nuclear membrane progressively deteriorates as an organism ages, removing this bulwark against genome instability.

Next, Dr. Chiolo and her team will explore how the movement of broken sequences is accomplished and regulated, and what happens in cells and organisms when this membrane-based repair mechanism fails. Their ultimate goal is to understand how this mechanism functions in human cells and identify new strategies to prevent their catastrophic failure and cancer formation.