The DNA Damage Response in Fully Grown Mammalian Oocytes

Abstract

DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and anomalies. If the damage occurs in the germline, it can potentially lead to infertility or chromosomal and genetic aberrations in the developing embryo. Mammalian oocytes, the female germ cells, are produced before birth, remaining arrested at the prophase stage of meiosis over a long period of time. During this extensive state of arrest the oocyte may be exposed to different DNA-damaging insults for months, years or even decades. Therefore, it is of great importance to understand how these cells respond to DNA damage. In this review, we summarize the most recent developments in the understanding of the DNA damage response mechanisms that function in fully grown mammalian oocytes.

Keywords: DNA damage response; DNA repair; checkpoints; oocyte.

Figure 1

The main repair pathways utilized by the eukaryotic cell.

Figure 2

States of arrest and checkpoints during mammalian oocyte maturation. The mammalian oocyte enters prophase arrest in embryonic life. Resumption of meiosis can occur after the onset of puberty. Following ovarian exposure to LH, the oocyte resumes meiosis, undergoes germinal vesicle breakdown (GVBD) and enters the first meiotic M-phase. After a lengthy prometahase I during which the first meiotic spindle is formed, homologous chromosome pairs align at the spindle equator. The Spindle Assembly Checkpoint (SAC) inhibits chromosome disjunction until all the chromosomes are properly attached to spindle microtubules from opposite spindle poles and under tension from pulling forces directed towards the poles. Chromosome segregation leads to an asymmetric meiotic division and immediate entry into meiosis II, where the oocyte arrests at metaphase II (MII) awaiting fertilization. Severe DNA damage imposed during prophase arrest launches the G2/prophase DNA damage checkpoint (DDC) which inhibits the resumption of meiosis. A damaged oocytes that slips through the DDC may become arrested during the first meiotic M-phase due to the activation of the SAC.

Figure 3

The DNA damage checkpoints in mammalian oocytes. DSBs that lead to severe DNA damage in prophase-arrested oocytes (GVs) launch an ATM/Chk1-dependent checkpoint which maintains prophase arrest. The G2/prophase checkpoint is not sensitive enough to detect moderate or low levels of damage. Potentially, prolonged GV culture or coculture with cumulus cells may maintain the state of arrest. Oocytes that enter the first meiotic M-phase in the presence of DNA damage either arrest in M-phase due to actions of the Spindle Assembly Checkpoint (SAC) or complete oocyte maturation and arrest at the second meiotic metaphase (MII) in the presence of DNA damage.