Role for the Silencing Protein Dot1 in Meiotic Checkpoint Control

Abstract

During the meiotic cell cycle, a surveillance mechanism called the "pachytene checkpoint" ensures proper chromosome segregation by preventing meiotic progression when recombination and chromosome synapsis are defective. The silencing protein Dot1 (also known as Pch1) is required for checkpoint-mediated pachytene arrest of the zip1 and dmc1 mutants of Saccharomyces cerevisiae. In the absence of DOT1, the zip1 and dmc1 mutants inappropriately progress through meiosis, generating inviable meiotic products. Other components of the pachytene checkpoint include the nucleolar protein Pch2 and the heterochromatin component Sir2. In dot1, disruption of the checkpoint correlates with the loss of concentration of Pch2 and Sir2 in the nucleolus. In addition to its checkpoint function, Dot1 blocks the repair of meiotic double-strand breaks by a Rad54-dependent pathway of recombination between sister chromatids. In vegetative cells, mutation of DOT1 results in delocalization of Sir3 from telomeres, accounting for the impaired telomeric silencing in dot1.

Histone H3 Lysine 36 Methylation Antagonizes Silencing in Saccharomyces cerevisiae Independently of the Rpd3S Histone Deacetylase Complex

“…Further, deletion of DOT1 suppresses the antisilencing phenotype of set2D in the reporter strain (Figure 3). This may be due to negative regulation of Dot1 by Set2, although it is more likely due to a general redistribution of Sir proteins throughout the genome in the absence of H3-K79 methylation, as has been observed by microscopy in spread mitotic and pachytene nuclei (San-Segundo and Roeder 2000).…”

SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes

“…In yeast, Sir2 maintains the silencing of the heterochromatin at the mating-type loci (3), telomeres (4), and rRNA-encoding DNA repeats (5). Furthermore, Sir2 is also involved in the repair of DNA double-strand breaks (6), cell cycle progression through anaphase, the meiotic chromosome segregation checkpoint (7), and the suppression of sister-chromatid recombination by recruiting cohesins (8). Most importantly, though, Sir2 mediates the effect of caloric restriction on life span extension (9).…”

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

“…Both DOT1 and the mammalian DOT1L (DOT1-like protein) function as H3K79 methyltransferases in the regulation of histone H3K79 methylation and transcriptional activation (19). In particular, DOT1/DOT1L-mediated H3K79 methylation is known to be involved in the control of transcriptional activity required for cell cycle, meiotic checkpoint, and the DNA damage checkpoint (20). It has also been reported that aberrant H3K79 methylation by DOT1L occurs in mixed lineage leukemia (MLL) (21).…”