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Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals.

ABSTRACT: Chromosome abnormalities are common in the human population, causing germ cell loss at meiotic prophase I and infertility. The mechanisms driving this loss are unknown, but persistent meiotic DNA damage and asynapsis may be triggers. Here we investigate the contribution of these lesions to oocyte elimination in mice with chromosome abnormalities, e.g. Turner syndrome (XO) and translocations. We show that asynapsed chromosomes trigger oocyte elimination at diplonema, which is linked to the presence of phosphorylated H2AFX (γH2AFX). We find that DNA double-strand break (DSB) foci disappear on asynapsed chromosomes during pachynema, excluding persistent DNA damage as a likely cause, and demonstrating the existence in mammalian oocytes of a repair pathway for asynapsis-associated DNA DSBs. Importantly, deletion or point mutation of H2afx restores oocyte numbers in XO females to wild type (XX) levels. Unexpectedly, we find that asynapsed supernumerary chromosomes do not elicit prophase I loss, despite being enriched for γH2AFX and other checkpoint proteins. These results suggest that oocyte loss cannot be explained simply by asynapsis checkpoint models, but is related to the gene content of asynapsed chromosomes. A similar mechanistic basis for oocyte loss may operate in humans with chromosome abnormalities.

SUBMITTER: Cloutier JM

PROVIDER: S-EPMC4624946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as CID in Drosophila . In Drosophila , CENP-C is critical for maintaining CID at the centromeres and directly recruits outer kinetochore proteins after nuclear envelope break down. It is not known, however, if these two functions require the same CENP-C molecules. Furthermore, in Drosophila and many other metazoan oocytes, centromere maintenance and kinetochore assembly are separated by an extended prophase. Consistent with studies in mammals, CID is relatively stable and does not need to be expressed during prophase to remain at high levels in metaphase I of meiosis. Expression of CID during prophase can even be deleterious, causing ectopic localization to non-centromeric chromatin, abnormal meiosis and sterility. In contrast to CID, maintaining high levels of CENP-C requires expression during prophase. Confirming the importance of this loading, we found CENP-C prophase loading is required for multiple meiotic functions. In early meiotic prophase, CENP-C loading is required for sister centromere cohesion and centromere clustering. In late meiotic prophase, CENP-C loading is required to recruit kinetochore proteins. CENP-C is one of the few proteins identified in which expression during prophase is required for meiotic chromosome segregation. An implication of these results is that the failure to maintain recruitment of CENP-C during the extended prophase in oocytes would result in chromosome segregation errors in oocytes.Author summaryMeiosis in oocytes of diverse organisms, including humans and Drosophila, is characterized by a long prophase pause and a cell cycle arrest in meiosis I or meiosis II. These pauses could be a challenge for centromeres, whose components are replenished during G1, and then must remain with the chromosomes until the meiotic divisions. We have investigated the stability, prophase dynamics and function of centromere protein CENP-C. We show that CENP-C expression and loading onto centromeres during prophase is required for multiple meiotic functions. In contrast, the expression of other centromere partners CID/CENP-A and CAL1 is not required during meiotic prophase. Furthermore, expression of CID during prophase can be deleterious and result in ectopic kinetochore formation. CENP-C loading in prophase is required for sister centromere cohesion and kinetochore assembly. Our results provide the first description of CENP-C dynamics during meiosis and show that prophase expression is required for oocyte spindle assembly and function. CENP-C is among a small number of proteins that are required for the meiotic divisions but are loaded prior to prometaphase. Failure to maintain these proteins during the long prophase of oocyte meiosis may contribute to the increased aneuploidy associated with advanced maternal age.

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Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals.

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