Functional characterization of KAISO and Kaiso knockout mice : apoptosis and testis atropy

Abstract

An unresolved issue regarding the response to genotoxic stress is identification of the regulatory protein(s) induced and determination of how they activate p53 to determine cell fate. KAISO has been previously described as a protein that represses transcription following binding to methylated DNA. In this study, I determined that its expression is induced by DNA damage prior to p53 expression. KAISO interacts with the p53-p300 complex to increase acetylation of the K320 and K382 lysine residues of p53, but not of the K381 residue. Acetylated p53 shows an increase in DNA binding specificity and activity of the p53 binding RRRCWWGYYY repeated motifs with no spacer and potently induces apoptosis by activating transcription of the CDKN1A and apoptotic genes. In Kaiso knockout (KO) MEF cells, transcription of apoptotic genes is significantly compromised. KAISO may therefore be a critical regulator of apoptosis in response to various genotoxic stresses in the mammalian cell. Spermatogenesis is a highly organized cyclic process with distinct phases: mitosis, meiosis and spermiogenesis. However, the molecular mechanisms of how spermatogonia, mitotic germ cells of the testis, self-renew and differentiate into sperm remain largely unknown. Here, we show that male Kaiso knockout mice are show testicular atrophy and infertile, and that Kaiso plays a major role in spermatogenesis by repressing Bcl6 transcription in spermatocytes. In adult Kaiso mouse knockout testes, Bcl6 expression is derepressed and represses transcription of the genes of the CREM pathway in spermatocytes, which results in without differentiation into spermatid and spermatozoa. Our study shows that Kaiso plays a critical role in spermatogenesis and may have significant implications to male infertility.