Infertility's roots in DNA packaging

March 26, 2019

Kyoto, Japan -- Pathological infertility is a condition affecting roughly 7% of human males, and among those afflicted, 10-15% are thought to have a genetic cause. However, pinpointing the precise genes responsible for the condition has been difficult, due to the extensive number involved in generating and developing sperm cells.

In a new paper appearing in Science Signaling, a Japanese team reports unravelling the mechanism behind one cause of infertility -- incomplete development of the proteins packaging DNA in sperm cells -- and further, success in making test mice fertile by replacing a single amino acid on a key protein.

In every cell, thread-like DNA is wound tightly in the nucleus around bobbin-like proteins called 'histones'. And in sperm cells -- the smallest humans produce -- another protein called 'protamine' is needed to wind the strands even tighter.

"It's been known for about 30 years that protamines are modified and matured during sperm development to enable proper functioning," explains first author Katsuhiko Itoh from Kyoto University's Graduate School of Medicine.

"This prompted us to disclose the underlying mechanism and biological consequences of protamine regulation, so that we can see how this process contributes to 'spermatogenesis' -- the making sperm cells."

The team focused on a series of chaperones: proteins that assist in processing other proteins. Detailed genetic analysis revealed that a chaperone known as Hspa4l is key to proper sperm cell development, and that its dysfunction has consequences similar to deficiency in a gene called Ppp1cc2.

"Further study showed that Hspa4l is vital for the proper functioning of phosphatase Ppp1cc2, a protein regulator," continues Itoh. "A dysfunction in Hspa41 stops Ppp1cc2 from reaching chromatin, resulting in failure to dephosphrylate protamine 2 at serine 56, and with protamine 2 not functioning, sperm cells don't develop."

With these data, the team produced a mouse in which serine 56 was substituted to alanine, dephosphomimetic of dephosphorylated serine: the single amino acid replacement that made all the difference. When combined with a mutation resulting in non-functioning Hspa41, the mouse showed no dysfunction in spermatogenesis, effectively preserving fertility.

Itoh emphasizes that his team's research shows the value in studying protamine modification in the process of sperm cell maturation. The group hopes to further unravel the complex network of gene interaction and protein modification in spermatogenesis, and its further implications for infertility.
-end-
The paper "Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo" appeared on 26 March 2019 in Science Signaling, with doi: 10.1126/scisignal.aao7232

About Kyoto University

Kyoto University is one of Japan and Asia's premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigious international prizes. A broad curriculum across the arts and sciences at both undergraduate and graduate levels is complemented by numerous research centers, as well as facilities and offices around Japan and the world. For more information please see: http://www.kyoto-u.ac.jp/en

Kyoto University

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.