Abstract
To protect germ cells from genomic instability, surveillance mechanisms ensure meiosis occurs properly. In mammals, spermatocytes that display recombination defects experience a so-called recombination-dependent arrest at the pachytene stage, which relies on the MRE11 complex—ATM—CHK2 pathway responding to unrepaired DNA double-strand breaks (DSBs). Here, we asked if p53 family members—targets of ATM and CHK2—participate in this arrest. We bred double-mutant mice combining a mutation of a member of the p53 family (p53, TAp63, or p73) with a Trip13 mutation. Trip13 deficiency triggers a recombination-dependent response that arrests spermatocytes in pachynema before they have incorporated the testis-specific histone variant H1t into their chromatin. We find that deficiency for either p53 or TAp63, but not p73, allowed spermatocytes to progress further into meiotic prophase despite the presence of numerous unrepaired DSBs. Even so, the double mutant spermatocytes apoptosed at late pachynema because of sex body deficiency; thus p53 and TAp63 are dispensable for arrest caused by sex body defects. These data affirm that recombination-dependent and sex body-deficient arrests occur via genetically separable mechanisms.
Highlights
The mammalian p53 family includes p53 [1,2], p63 [3] and p73 [4], which are transcription factors encoded by three highly conserved genes [5,6]
At the onset of the first meiotic division, SPO11 protein introduces double-strand breaks (DSBs) throughout the genome. These DSBs are repaired through homologous recombination, which promotes pairing and synapsis of the homologous chromosomes
The majority of apoptotic spermatocytes in the p53 and TAp63 double mutants were H1t-positive (Fig 2E–2H and 2I and S4A–S4D Fig). These results indicate that both p53 and TAp63, but not p73, promote the elimination of most spermatocytes with numerous unrepaired DSBs in early pachynema
Summary
The mammalian p53 family includes p53 [1,2], p63 [3] and p73 [4], which are transcription factors encoded by three highly conserved genes [5,6]. Each member has three major domains: an amino-terminal transactivation (TA) domain, a central DNA binding domain, and a carboxy-terminal oligomerization domain [5,7]. Alternative promoters express two isoforms of p63 and p73. The transactivating isoforms contain the TA domain and the ΔN isoforms lack it [7,8]. The TA isoforms tend to have tumor suppressor activities, while the ΔN isoforms act as dominant-negative inhibitors that can bind DNA but do not promote transcription [5,7,8]. Splicing variation at the 30 end of the mRNAs generates additional isoforms [5,8,9]
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