title: Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling.
abstract: Genome maintenance in germ cells is critical for fertility and the stable propagation of species. While mechanisms of meiotic DNA repair and chromosome behavior are well-characterized, the same is not true for primordial germ cells (PGCs), which arise and propagate during very early stages of mammalian development. Fanconi anemia (FA), a genomic instability syndrome that includes hypogonadism and testicular failure phenotypes, is caused by mutations in genes encoding a complex of proteins involved in repair of DNA lesions associated with DNA replication. The signaling mechanisms underlying hypogonadism and testicular failure in FA patients or mouse models are unknown. We conducted genetic studies to show that hypogonadism of Fancm mutant mice is a result of reduced proliferation, but not apoptosis, of PGCs, resulting in reduced germ cells in neonates of both sexes. Progressive loss of germ cells in adult males also occurs, overlaid with an elevated level of meiotic DNA damage. Genetic studies indicated that ATM-p53-p21 signaling is partially responsible for the germ cell deficiency.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Yunhai
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Hartford
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Ruizhu
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Southard
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shima
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D042822:Genomic Instability; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D020741:rho GTP-Binding Proteins