Running the gauntlet: challenges to genome integrity in spermiogenesis

Abstract

Species' continuity depends on gametogenesis to produce the only cell types that can transmit genetic information across generations. Spermiogenesis, which encompasses post-meiotic, haploid stages of male gametogenesis, is a process that leads to the formation of sperm cells well-known for their motility. Spermiogenesis faces three major challenges. First, after two rounds of meiotic divisions, the genome lacks repair templates (no sister chromatids, no homologous chromosomes), making it incredibly vulnerable to any genomic insults over an extended time (typically days-weeks). Second, the sperm genome becomes transcriptionally silent, making it difficult to respond to new perturbations as spermiogenesis progresses. Third, the histone-to-protamine transition, which is essential to package the sperm genome, counterintuitively involves DNA break formation. How spermiogenesis handles these challenges remains poorly understood. In this review, we discuss each challenge and their intersection with the biology of protamines. Finally, we discuss the implication of protamines in the process of evolution.

Keywords: DNA damage; Double stranded breaks (DSB); Spermiogenesis; genome integrity; protamines.

Figure 1.

Cellular and genomic changes during spermiogenesis. (a) Sperm undergo dramatic morphological differentiation from round haploid cells after meiosis to elongated nuclei with flagellar tails (top). Meanwhile, the genome first becomes haploid after meiosis, and then changes genomic architecture as histones are exchanged for protamines. Importantly, cells in meiosis I or II have homologous chromosomes or sister chromatids that provide 3 or 1 DNA templates, respectively, for potential DNA repair (bottom). Note that homologous recombination is not depicted in this cartoon. (b-d) Spermiogenesis contains 3 major challenges to genome integrity (see main text).

Figure 2.

Potential solution to spermiogenesis challenges. (a) If developing sperm are damaged during spermiogenesis, how are they be detected and what is their fate? (b) We propose that a novel checkpoint could exist that does not rely on canonical transcription-based responses, nucleosomes and histone modifications, or a second DNA template.

Figure 3.

Hypothetical example of co-evolution between DNA sequences and protamines. (a) Perhaps protamines have preferential affinity for repetitive sequences, which could provide a signal to create DSBs safely at repetitive sequences so that genic sequences are not mutated but can incorporate protamines. (b) This preferential affinity could evolve to be sequence-specific such that the ‘wrong’ protamine-DNA pair cannot compact, causing interference with and ultimately failure of the histone-to-protamine transition.