The Spartan Ortholog Maternal Haploid Is Required for Paternal Chromosome Integrity in the Drosophila Zygote

Abstract

The animal sperm nucleus is characterized by an extremely compacted organization of its DNA after the global replacement of histones with sperm-specific nuclear basic proteins, such as protamines. In the absence of DNA repair activity in the mature gamete, the integrity of the paternal genome is potentially challenged by the unique topological constraints exerted on sperm DNA. In addition, the maintenance of paternal DNA integrity during the rapid remodeling of sperm chromatin at fertilization has long been regarded as a maternal trait. However, little is known about the nature of the egg proteins involved in this essential aspect of zygote formation. We had previously characterized the unique phenotype of the classical Drosophila maternal effect mutant maternal haploid (mh), which specifically affects the integration of paternal chromosomes in the zygote. Here we show that MH is the fly ortholog of the recently identified human DVC1/Spartan protein, a conserved regulator of DNA damage tolerance. Like Spartan, MH protein is involved in the resistance to UV radiation and recruits the p97/TER94 segregase to stalled DNA replication forks in somatic cells. In the zygote, we found that the mh phenotype is consistent with perturbed or incomplete paternal DNA replication. Remarkably, however, the specific accumulation of MH in the male pronucleus before the first S phase suggests that this maternal protein is required to maintain paternal DNA integrity during nuclear decondensation or to set the paternal chromatin landscape in preparation of the first zygotic cycle.

Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN

“…Moreover, premature cataract has been observed in RJALS and in a hypomorphic SPRTN mouse model, which is a general sign of failure to maintain postmitotic tissue homeostasis (Maskey et al., 2014, Ruijs et al., 2003). A replication-independent function of SPRTN also is indicated by results in flies, where SPRTN is recruited to chromatin independently of replication (Delabaere et al., 2014). Consistently, we found that arrested L1 worm larvae, in which no replication is occurring, are extremely sensitive to acute formaldehyde exposure if they lack SPRTN.…”

“…Initial studies suggested that SPRTN is important for regulating translesion synthesis (TLS), although with conflicting reports on the actual molecular mechanism (Centore et al., 2012, Davis et al., 2012, Ghosal et al., 2012, Juhasz et al., 2012, Machida et al., 2012, Mosbech et al., 2012). Importantly, however, the severe phenotypes observed in flies, mice, and human cells have been shown to be unrelated to TLS, suggesting that SPRTN maintains genome integrity by an unknown mechanism distinct from TLS (Delabaere et al., 2014, Lessel et al., 2014, Maskey et al., 2014). …”

Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis

“…Consistent with this interpretation, our previous study identified interactions between the Spartan SprT domain and DNA polymerase δ (8). On the other hand, a DNA replication-independent function of Spartan has also been suggested in C. elegans and D. melanogaster (20,53). Thus, it remains unclear whether the Spartan-dependent DPC repair pathway is always coupled with DNA replication.…”

DNA–protein crosslink repair

“…However, recent studies have revealed additional, crucial functions of SPRTN in maintaining genome stability, supposedly independently of TLS. Loss of function of Drosophila melanogaster Sprtn causes the elimination of paternal genomes after fertilization owing to excessive genome instability 54 . The authors postulated that packaging of paternal DNA within the sperm induces specific types of DNA damage, which need to be repaired to allow proper replication and faithful chromosome segregation.…”