Poly(ADP-ribose) Metabolism Is Essential for Proper Nucleoprotein Exchange During Mouse Spermiogenesis

Abstract

Sperm chromatin is organized in a protamine-based, highly condensed form, which protects the paternal chromosome complement in transit, facilitates fertilization, and supports correct gene expression in the early embryo. Very few histones remain selectively associated with genes and defined regulatory sequences essential to embryonic development, while most of the genome becomes bound to protamine during spermiogenesis. Chromatin remodeling processes resulting in the dramatically different nuclear structure of sperm are poorly understood. This study shows that perturbation of poly(ADP-ribose) (PAR) metabolism, which is mediated by PAR polymerases and PAR glycohydrolase in response to naturally occurring endogenous DNA strand breaks during spermatogenesis, results in the abnormal retention of core histones and histone linker HIST1H1T (H1t) and H1-like linker protein HILS1 in mature sperm. Moreover, genetic or pharmacological alteration of PAR metabolism caused poor sperm chromatin quality and an abnormal nuclear structure in mice, thus reducing male fertility.

Post-Meiotic DNA Damage and Response in Male Germ Cells

“…At least four independent sensors can detect DSBs: PARPs in all cases of SSBs and, to a lesser extent, DSBs, Ku70/80 in D-NHEJ, MRE11-RAD50-NBS1 (MRN) complex in all cases of DSBs and replication protein A1 (RPA) in HR (Ciccia and Elledge, 2010;Lamarche et al, 2010). As previously stated in section 3.2.3, the presence and activity of PARP1 and PARP2 have been recently investigated during spermiogenesis of mouse and rat (Ahmed et al, 2010;Dantzer et al, 2006;Meyer-Ficca et al, 2005;Meyer-Ficca et al, 2011a;Meyer-Ficca et al, 2009;Meyer-Ficca et al, 2011b). Although the individual absence of these proteins leads only to subfertility in male, it is believed that they play a key role in the maintenance of genomic integrity of spermatids.…”

“…Moreover, alteration in the PAR metabolism leads to a greater retention of histones in spermatozoa (Meyer-Ficca et al, 2011a). Whether PARP1 is involved directly in chromatin remodeling, DNA repair or combination of both in spermatids remains to be determined and will be discussed further in section 4.…”

DNA repair systems

“…Poly-(ADP-ribose)-polymerase 1 ac vity was found to play a crucial role in mammalian meiosis and gamete selec on through apoptosis [892,905,906]. In mice, Parp1 ac vity has been found to be essen al for normal spermatogenesis [907]. During spermatogenesis, the reorganisa on of a diploid, histone-associated genome into a haploid, predominantly protamine-associated genome is accompanied by occurrence of physiological DNA strand breaks, which exist only temporarily [908].…”

Feux croisés sur le nucléosome

“…En effet, différents auteurs ont mis en évidence une association entre l'élongation des spermatides et une modification globale des histones. Il s'agit de la mono-ubiquitinylation de l'histone H2A [23], de l'accumulation des polymères d'ADPribose et de la phosphorylation du variant H2AX [24][25][26]. Une question importante est de savoir pourquoi toutes ces modifications d'histones s'accumulent pendant la période de dissociation des nucléosomes et de retrait des histones ?…”