Lsd1 and Lsd2 Control Programmed Replication Fork Pauses and Imprinting in Fission Yeast

Abstract

In the fission yeast Schizosaccharomyces pombe a chromosomal imprinting event controls the asymmetric pattern of mating-type switching. The orientation of DNA replication at the mating-type locus is instrumental in this process. However, the factors leading to imprinting are not fully identified and the mechanism is poorly understood. Here we show that the replication fork pause at the mat1 locus (MPS1), essential for imprint formation, depends on the lysine specific demethylase, Lsd1. We demonstrate that either Lsd1 or Lsd2 amine oxidase activity is required for these processes, working upstream of the imprinting factors Swi1 and Swi3 (homologs of mammalian Timeless and Tipin, respectively). We also show that the Lsd1/2 complex controls the replication fork terminators, within the rDNA repeats. These findings reveal a novel role for the Lsd1/2 demethylases in controlling polar replication fork progression, imprint formation and subsequent asymmetric cell divisions.

Dicer Promotes Transcription Termination at Sites of Replication Stress to Maintain Genome Stability

“…The histone demethylase Lsd1 is required for replication fork pausing within rDNA (Holmes et al, 2012), and is enriched at tDNA (Lan et al, 2007) where it may also play the same role, as H3K9me2 spreads across tRNA boundaries in lsd1 mutants (Lan et al, 2007) and depends on association of CLRC with the replisome (Li et al, 2011; Zaratiegui et al, 2011). We hypothesized that in the absence of programmed fork pausing, collisions between Pol II and replication forks would increase, and that Dcr1 would be required to resolve these.…”

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

“…The moving fork pauses at MPS1 , generating the essential imprint that initiates a replication-coupled recombination process, leading to the mating-type switch event [134,135]. Other trans -acting factors are necessary for mating-type switching; replication fork pausing at MPS1 is dependent on Lsd1 and Lsd2 (Figure 5) [136], lysine-specific demethylases that are required for demethylation of histone H3 at its lysine 4 (H3K4) and lysine 9 (H3K9) residues for transcriptional regulation [137,138,139]. Lsd1 and Lsd2 appear to work upstream of the FPC to pause replication forks because recruitment of Swi1 at MPS1 is significantly reduced in the lsd1 -mutant [136].…”

“…Other trans -acting factors are necessary for mating-type switching; replication fork pausing at MPS1 is dependent on Lsd1 and Lsd2 (Figure 5) [136], lysine-specific demethylases that are required for demethylation of histone H3 at its lysine 4 (H3K4) and lysine 9 (H3K9) residues for transcriptional regulation [137,138,139]. Lsd1 and Lsd2 appear to work upstream of the FPC to pause replication forks because recruitment of Swi1 at MPS1 is significantly reduced in the lsd1 -mutant [136]. Interestingly, Lsd1 and Lsd2 are also required at other FPC-mediated fork pausing sites including RTS1 and RFBs at rDNA repeats, suggesting a role for either of these demethylases in FPC-dependent fork pausing.…”

A Unique DNA Recombination Mechanism of the Mating/Cell-type Switching of Fission Yeasts: a Review

“…5): Sap1 (38), Swi1, Swi3, and Swi7 (24), and the lysine-specific demethylases Lsd1 and Lsd2 (39). The first trans-acting factor identified as essential for imprinting was the catalytic subunit of DNA polymerase α encoded by swi7 (40).…”