Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, Bonn, Germany.
PLoS Genet. 2022 Jun 28;18(6):e1010272. doi: 10.1371/journal.pgen.1010272. eCollection 2022 Jun.
Protamines are unique sperm-specific proteins that package and protect paternal chromatin until fertilization. A subset of mammalian species expresses two protamines (PRM1 and PRM2), while in others PRM1 is sufficient for sperm chromatin packaging. Alterations of the species-specific ratio between PRM1 and PRM2 are associated with infertility. Unlike PRM1, PRM2 is generated as a precursor protein consisting of a highly conserved N-terminal domain, termed cleaved PRM2 (cP2), which is consecutively trimmed off during chromatin condensation. The carboxyterminal part, called mature PRM2 (mP2), interacts with DNA and together with PRM1, mediates chromatin-hypercondensation. The removal of the cP2 domain is believed to be imperative for proper chromatin condensation, yet, the role of cP2 is not yet understood. We generated mice lacking the cP2 domain while the mP2 is still expressed. We show that the cP2 domain is indispensable for complete sperm chromatin protamination and male mouse fertility. cP2 deficient sperm show incomplete protamine incorporation and a severely altered protamine ratio, retention of transition proteins and aberrant retention of the testis specific histone variant H2A.L.2. During epididymal transit, cP2 deficient sperm seem to undergo ROS mediated degradation leading to complete DNA fragmentation. The cP2 domain therefore seems to be a key aspect in the complex crosstalk between histones, transition proteins and protamines during sperm chromatin condensation. Overall, we present the first step towards understanding the role of the cP2 domain in paternal chromatin packaging and open up avenues for further research.
鱼精蛋白是一种独特的精子特异性蛋白，它将父本染色质包装并保护起来，直到受精。哺乳动物的一个亚类表达两种鱼精蛋白（PRM1 和 PRM2），而在其他亚类中，PRM1 足以包装精子染色质。PRM1 和 PRM2 之间的物种特异性比例的改变与不孕有关。与 PRM1 不同，PRM2 作为一种前体蛋白产生，由高度保守的 N 端结构域组成，称为切割的 PRM2（cP2），在染色质浓缩过程中连续被修剪掉。羧基末端部分，称为成熟的 PRM2（mP2），与 DNA 相互作用，并与 PRM1 一起介导染色质超浓缩。cP2 结构域的去除被认为对正确的染色质浓缩是至关重要的，但 cP2 的作用尚不清楚。我们生成了缺乏 cP2 结构域而 mP2 仍表达的小鼠。我们表明，cP2 结构域对于完整的精子染色质鱼精蛋白化和雄性小鼠生育能力是必不可少的。cP2 缺乏的精子显示不完全的鱼精蛋白掺入和严重改变的鱼精蛋白比例，过渡蛋白的保留和睾丸特异性组蛋白变体 H2A.L.2 的异常保留。在附睾转运过程中，cP2 缺乏的精子似乎经历 ROS 介导的降解，导致完全的 DNA 碎片化。因此，cP2 结构域似乎是在精子染色质浓缩过程中组蛋白、过渡蛋白和鱼精蛋白之间复杂相互作用的关键方面。总的来说，我们朝着理解 cP2 结构域在父本染色质包装中的作用迈出了第一步，并为进一步的研究开辟了途径。
