Tumor suppressor properties and a role in maintaining genome integrity for the Meig1 gene (736.3)

Abstract

Meig1 is a highly conserved gene first identified in mouse pachytene spermatocytes undergoing meiotic recombination. In these cells the MEIG1 protein enters the nucleus and forms foci along the meiotic chromosomes, reminiscent of foci obtain by proteins known to be involved in the DNA damage response. Meig1 knockout (KO) male mice are infertile. These mice exhibit increased apoptosis of post recombination spermatogenic cells and significantly fragmented DNA in the few epididymal sperm cells that could be obtained. Given these findings the objectives of this study were to examine the hypothesis that MEIG1 plays a role in the system responsible for maintaining genome integrity. Immunocytochemistry analysis of γH2AX signaling in meiotic chromosomes of late pachytene spermatocytes showed that in KO mice they were highly “decorated” with γH2AX foci, compared to WT chromosomes. Moreover, analysis of post‐recombination meiotic chromosomes revealed the existence of numerous chromosomal fragments in KO meiotic preparations whereas no such fragments could be seen in preparations from WT spermatocytes. Regarding somatic cells, KO MEFs exposed to etoposide treatment exhibited significantly slower disappearance of the γH2AX foci compare to WT MEFs, suggesting delayed or aberrant repair. Interestingly, most Meig1 KO mice (more than 30 mice to date), and about one third of the Meig1 +/‐ heterozygotes developed huge and aggressive tumors between 6‐18 months of age, whereas none of the age‐matched wild‐type (WT) siblings developed tumors. These tumors were identified as being mainly malignant adeno‐carcinomas and lymphomas. These results imply that Meig1 has tumor suppressive properties and suggest that it is involved in maintaining chromatin integrity not only in spermatogenic cells but in somatic cells as well, rendering it as a new player in the general DNA damage response, especially the response to DSB.This study was supported by grant No. 20072019B from the Israel Cancer Association.