more than a century ago, scientists found a strange phenomenon in animal sperm: the absolute dominance of animals in the body is somatic cells. In their nuclei, the genome DNA is often twisted into a "stick" axis, and the core of the "spool" is the aggregate of the histone, eight histone. But in mature spermatozoa, it is another case. Histones in the nuclei of mature spermatozoa are replaced by protamine.
the purpose of this "replacement" seems to be to sharpen the "head" of the sperm. A denser "spool" is designed to ensure genetic stability. And only when this "replacement" is successfully completed can sperm become energized. Otherwise, the sperm will be "out of shape" with low swimming ability and even no vitality.
how does this "replacement" process take place, and what genes, proteins or other intracellular substances participate in it? Little is known.
until 2010, scientists found that replacement of H2A and H2B histone only occurred when the "spool" was ubiquitin. The histone ubiquitin ligase, known as RNF8, regulates this process, because the ubiquitination tag of H2A and H2B is added to it.
ubiquitin is a small molecular weight protein in cells. It is like a countdown card, once a series of ubiquitin is "hung" on a protein, such as the histone, indicating that the histone is going to "end up" and be cleaned to the "dump".
but who controlled RNF8? Who triggered the "replacement" process?
people know nothing about it.
turn up about three years ago. In 2013, the team led by Liu Mofang made new discoveries on the protein research of the PIWI family. The
self destruct domain D-box failure
the structure of the protein of the PIWI family as a biological macromolecule, divided into four domains (domain), including the "amino end". For a long time, the function of its amino terminal is unknown.
Liu Mofang team first discovered that the amino terminal of the family protein existed D-box domain (self destruction domain, destruction box). From its name, people may think of the animated scene of "rotating in situ and exploding on its own". Related studies confirm that the D-box domain is indeed related to the normal clearance of PIWI family proteins, such as HIWI protein and MIWI protein.
sperm production and maturation process.
three of the above patients with azoospermia had mutations in the Hiwi gene corresponding to the D-box domain occurring in the HIWI protein. The dysfunction of this functional domain leads to the fact that HIWI protein is not able to be eliminated in the late stage of spermatozoa transformation. What are the effects of
D-box domain exceptions on RNF8?
researchers conducted further studies in mice. In mice, the PIWI protein corresponding to HIWI is known as "MIWI protein".
Gou Lantao and Dai Peng of Liu Mofang team discovered that MIWI protein can bind to RNF8 protein and cause RNF8 to remain in the cytoplasm.
normally, when the sperm is deformed and the sperm will be mature, the MIWI protein will be removed, RNF8 can be nucleed, and its ubiquitin ligase function is played, so that the histone in the nucleus of the DNA "spool" in the nucleus of the sperm is ubiquitin.
however, when the researchers introduced the Piwi gene mutation into mice, these mutant genes encoded the abnormal MIWI protein in the D-box domain. The protein can not be removed normally at the stage of sperm maturation, resulting in the persistent retention of RNF8 in the cytoplasm, which leads to the lack of ubiquitination of the histone in the sperm nucleus. The lack of ubiquitin labeling causes sperm DNA "spool" to fail and its histone is not replaced by protamine.
this great change allows the mature sperm cells to stay at puberty forever - morphologic deformities, lack of a sharp head, and poor vitality. The end result is that there is no mature, functional and qualified spermatozoa in the semen of these patients, resulting in azoospermia and male infertility.
researchers found that when they use the RNF8-N peptide to consume the abnormal MIWI protein in sperm cells and prevent the protein from intercepting RNF8, the sperm cells will be saved, successfully through puberty, mature and full of vitality.
, of course, the researchers emphasized whether the intervention could become a universal treatment method, which still needs practical consideration.