H2AFX and MDC1 Protect Genomic Integrity in Male Germ Cells by Promoting Recombination and Activation of the Recombination-Dependent Checkpoint

In somatic cells,H2afxandMdc1are close functional partners in DNA repair and damage response. However, it is not known whether they are also involved in the maintenance of genome integrity in meiosis. By analyzing chromosome dynamics inH2afx-/-spermatocytes, we found that synapsis of the autosomes and X-Y chromosomes were impaired in a relevant fraction of cells. Such defect correlated with an abnormal recombination profile. Conversely,Mdc1was dispensable for the synapsis of the autosomes, and only played a minor role in X-Y synapsis, relatively toH2afx. This suggested that those genes have non-overlapping functions in chromosome synapsis. However, we observed that both genes play a similar role in the assembly of MLH3 onto chromosomes, a key step in crossover formation. Moreover, we showed thatH2afxandMdc1cooperate in promoting the activation of the recombination-dependent checkpoint, a mechanism that restrains the differentiation of cells with unrepaired DSBs. This occurs by a mechanism that involves P53. Overall, our data showed that, in male germ cells,H2afxandMdc1promote the maintenance of genome integrity.