A study conducted in 2007 revealed a protein, Chd5, re-organizes the DNA of a cell in a way that stops development of cancerous tumors. More recent studies by the research team that identified Chd5 and its effect on tumor growth indicate an absence of the protein affects sperm quality and contributes to male infertility just as its absence affects cancer development.
Professor Alea Mills and her team of researchers at the Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, have determined that Chd5 is essential for transporting paternal DNA to an egg for fertilization. The research team likens the interaction of DNA and Chd5 to a spool and thread.
Spool and Thread
Inside every cell in the body is a copy of the entire human genome (DNA). This genetic material, in the form of a double helix, is tightly compressed within the cell but there’s so much of it, that if it were unspooled, the DNA from a single cell would be about six feet long.
Tiny protein spools called histones control chromatin in the cell, winding it or unwinding it as needed. Chromatin is the material that holds together the DNA, RNA, and proteins in each cell‘s nucleus. Histones organize the chromatin in useful order.
The sperm cell, at 1/500th of an inch, is one of the smallest in the body. The DNA it carries must be compacted much more tightly than in other cells. To achieve the most tightly compacted DNA, histones are replaced by protamines in a process called chromatin remodeling. The Mills research team considers chromatin remodeling absolutely essential for male reproductive health.
Knowing that Chd5 reorganizes DNA in a way that promotes or prohibits tumor growth, the team wanted to test its effect, if any, on “the most dramatic chromatin reorganization” of all — when specialized cells reorganize DNA for transport by sperm cells. Their study involved male mice.
Chd5 and Male Fertility
As with people, mice inherit genes for Chd5 from mother and father. When these genes were removed, the mice developed severe reproductive disorders. The research team discovered multiple factors of male infertility, including low sperm count and decreased sperm motility. Every attempt at in vitro fertilization failed.
Mills’ research team discovered that the absence of Chd5 leads to disruption of chromatin remodeling. During the DNA-organizing process to prepare genetic materials for sperm cells, protamines did not replace histones. The chromatin was not effectively compacted and was unevenly wound around protein spools. This disarray damaged the DNA’s double helix, causing it to break at intervals throughout the genome.
In tests of Chd5 in biopsied tissue of the testes of infertile human males, the Mills team discovered low levels of Chd5 in the men with the most severe reproductive defects. In addition to its effect on male infertility, Mills suggests healthy levels of Chd5 might protect against diseases such as autism, which is linked to spontaneous mutation and DNA damage.
Source: Mills, Alea A, et al. “Chd5 orchestrates chromatin remodeling during sperm development.” Nature Communications. Nature Publishing Group. May 13, 2014. Web. Jun 10, 2014.