Histone acetyltransferase and genetic integrity of the male gamete

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The male and female gametes are the basis of a new individual and their intact genomes ensure faithful transmission of genetic information to the next generation. The production of the male gamete during spermatogenesis is a complex differentiation process. The haploid phase of this process termed "spermiogenesis" is characterized by an important restructuring of the chromatin involving a major change in DNA packaging. We have clearly demonstrated that in both mouse and humans transient DNA strand breaks appear in the whole population of sperm cells precursors (spermatids) and are coincident with the major steps of chromatin remodeling. Any occurrence of transient strand breakage represents a potential threat to DNA integrity and the mutagenic potential of this important step of chromatin remodeling has been so far overlooked. Perturbations in the process can lead to genetic alterations with dramatic consequences for fertility or genetic disorders of the embryo. During spermiogenesis, the histones, which normally package DNA, are withdrawn following a biochemical modification (acetylation). Acetylation is though to create a transient state of DNA sensitivity allowing strand breakage. We identified a novel enzyme able to acetylate histone and that may play a role in the formation of DNA strand breaks. This enzyme, termed lysophosphatidic acid acyltransferase alpha (LPAATalpha), is normally involved in lipid metabolism but is now surprisingly found in the nuclei of spermatids. This project aims to study the new nuclear role of LPAATalpha and other acyltransferases in controlling histone acetylation and the formation of DNA breaks linking for the first time lipid metabolism to chromatin dynamics.