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.
Highlights
Fanconi anemia (FA) is a genomic instability (GIN) syndrome characterized by developmental abnormalities affecting the renal, gastrointestinal and reproductive systems, the skeleton, skin pigmentation, and heart
It causes progressive bone marrow failure and increased incidence of cancer [1,2]. It can be caused by germline mutations in any of at least 17 genes (FANCA, FANCB, FANCC, FANCD1(BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN (PALB2), FANCO(RAD51C), FANCP(SLX4), FANCQ(ERCC1 or 4)) [3,4])
The precursors to sperm and eggs begin are a group of, 100 cells in the embryo, called primordial germ cells (PGCs). They migrate in the primitive embryo to the location of the future gonads, undergo a rapid proliferation over the few days to a population of many thousands. Because these cells contain the precious genetic information for our offspring, and the DNA replication associated with rapid PGC proliferation is subject to spontaneous errors, mechanisms exist to avoid propagation of mutations
Summary
Fanconi anemia (FA) is a genomic instability (GIN) syndrome characterized by developmental abnormalities affecting the renal, gastrointestinal and reproductive systems, the skeleton, skin pigmentation, and heart. It causes progressive bone marrow failure and increased incidence of cancer [1,2] It can be caused by germline mutations in any of at least 17 genes (FANCA, FANCB, FANCC, FANCD1(BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN (PALB2), FANCO(RAD51C), FANCP(SLX4), FANCQ(ERCC1 or 4)) [3,4]). The products of these genes coordinately function in the repair of DNA interstrand crosslinks (ICL) during DNA replication [5]. FANCM has translocase activity that promotes branch migration of Holliday junctions and replication forks independent of FAAP24 [12]
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