Crucial role of sperm DNA-packaging protein has been identified in mice, which causes infertility when truncated.
During sperm production in humans, 23 DNA chromatin strands must be tightly wound into the head of the sperm. Because sperm cells are significantly smaller than typical human cells, sperm-specific proteins called protamines are required to tightly package and protect DNA during this process. Now, researchers from Germany have identified a previously unknown mechanism by which protamine 2 (PRM2) is required for fertility in mice.
'Most mammals seem to produce only one type of protamine, PRM1. In humans, but also rodents like mice, it's different – they have a second type, PRM2', said first-author of the study, Dr Lena Arevalo, University of Bonn, Germany.
DNA is normally packaged more loosely around histone proteins, however, during sperm generation, histones are replaced by protamines. The N-terminal domain of PRM2 is normally cleaved during sperm DNA packaging. In this study, published in PLOS Genetics, the authors generated a mouse model in which the PRM2 N-terminal domain was absent, leaving only a truncated protein behind. This led to inefficient transfer of DNA from histones to protamines, and ineffective DNA packaging into sperm.
Importantly, when mutant male mice which have only the truncated form of PRM2 were mated with healthy female mice, no offspring were produced. The mice were infertile.
'Proper PRM2 cleaving, therefore, seems to be crucial for successful reproduction, yet, the function of the [PRM2 N-terminal] domain and PRM2 processing are unknown to date' the authors explained in their paper.
Further biochemical analysis showed that the sperm of these mice had impaired motility, abnormal shape and their DNA was fragmented, highlighting the importance of an intact N-terminal domain of PRM2.
Unlike other species, having this second protamine is specific to mice and primates. As this DNA packaging process is thought to occur using similar mechanisms in humans, the researchers hypothesise that having a faulty PRM2 protein may cause infertility in men.
'We were able to provide a first glimpse into the function of cleaved PRM2 and PRM2 processing, that opens up multiple avenues for further investigation', concluded the authors.