High impact information on PDS1

• The separation of sister chromatids at the metaphase-to-anaphase transition is triggered by a protease called separase that is activated by the destruction of an inhibitory chaperone (securin) [1].
• In vitro, Mnd2 inhibits ubiquitination of Pds1 by APC/C-Ama1 but not by other APC/C holo-enzymes [2].
• Cells regulate anaphase entry by delaying securin ubiquitination until all chromosomes have attached to the mitotic spindle [3].
• Though no longer regulated by this mitotic surveillance mechanism, sister separation remains tightly cell cycle regulated in yeast mutants lacking securin [3].
• An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast [4].

Biological context of PDS1

• This metaphase block was partially relieved by a deletion of PDS1 [5].
• Previous studies indicate that RAD9 is required for X-ray-associated sister chromatid exchange (SCE), suppresses homology-directed translocations, and is involved in pathways for double-strand break repair (DSB) repair that are different than those controlled by PDS1 [6].
• We show that destruction of Pds1p is the APC's sole role in triggering Scc1p's dissociation from chromatids and that Pds1p forms a stable complex with a 180 kDa protein called Esp1p, which is essential for the dissociation of Scc1p from sister chromatids and for their separation [4].
• Inappropriate attachment/tension between chromosomal kinetochores and the kinetochore microtubules activates the spindle assembly checkpoint, which delays anaphase by blocking the ubiquitin-mediated degradation of securin/Pds1p by APC(Cdc20) [7].
• In contrast, Rad53p and Chk1p, needed for the stabilization of Pds1p in the context of the G2 DNA-damage checkpoint pathway, are dispensable [8].

Anatomical context of PDS1

• PtdSer (phosphatidylserine) is synthesized in the endoplasmic reticulum and the related MAM (mitochondria-associated membrane), and transported to the PtdSer decarboxylases, Pds1p in the mitochondria, and Psd2p in the Golgi [9].

Associations of PDS1 with chemical compounds

• To determine the role of PDS1 in recombinational repair pathways, we measured spontaneous and DNA damage-associated sister chromatid exchanges (SCEs) after exposure to X rays, UV and methyl methanesulfonate (MMS) and after the initiation of an HO endonuclease-generated double-strand break (DSB) [10].
• Thus, Pds1 mutant yeast cells display precocious sister chromatid separation in the presence of nocodazole [6] [11].
• This does not, however, exclude an essential S-phase checkpoint function of Pds1 beyond the early S-phase arrest point of a HU block [12].
• At the metaphase to anaphase transition, separin is activated by proteolysis of its inhibitory subunit (securin) called Pds1 [13].
• Levels of Pds1, an inhibitor of anaphase that accumulates following DNA damage, were similar in the wild-type and mutant strains following MMS treatment [14].

Physical interactions of PDS1

• Pds1p was also stabilized by the overexpression of Ibd2p in wild-type cells [15].
• Here we find that Pds1 interacts directly with Cdc20 and that this interaction requires Pds1's destruction box [16].

Enzymatic interactions of PDS1

• Here, we show that Pds1 is phosphorylated at multiple sites in vivo in response to DNA damage by Chk1 [17].

Regulatory relationships of PDS1

• Mec1p regulates Pds1p levels in S phase: complex coordination of DNA replication and mitosis [8].
• Yeast Chk1p kinase regulates the metaphase-to-anaphase transition in the DNA-damage checkpoint pathway via securin (Pds1p) phosphorylation [18].
• Mutants affecting the Chk1-Pds1 metaphase-anaphase checkpoint only suppressed tpp1 apn1 rad1 slow growth [19].
• What triggers Pds1p proteolysis and why does it not also trigger that of Clb2p [20]?
• Cdc20p may promote the APC-dependent proteolytic degradation of Pds1p and other factors that act to inhibit cell cycle progression through mitosis [21].

Other interactions of PDS1

• We propose that the APC promotes sister separation not by destroying cohesins but instead by liberating the "sister-separating" Esp1 protein from its inhibitor Pds1p [4].
• How the parallel pathways might interact ultimately to achieve arrest is not yet understood, but we do provide evidence that neither the RAD53 nor the PDS1 pathway appears to maintain arrest by inhibiting adaptation [22].
• RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast [22].
• While the G(1)/S block in both cdc4-12 and cdc4Delta mutants is abolished by the deletion of the SIC1 gene (causing the mutants to be arrested predominantly in G(2)/M), the preanaphase arrest in the cdc4-12 mutant is relieved by the deletion of PDS1 [23].
• Therefore, Rad23p and Ddi1p participate in a subset of Pds1p-dependent cell cycle controls [24].

Analytical, diagnostic and therapeutic context of PDS1

• Pds1 and Mcd1/Scc1 stability is measured in populations by Western blots [25].
• The metaphase to anaphase transition is assayed by monitoring sister chromatid separation using GFP-tagged chromosomes, Pds1 stability using immunofluorescence, and Mcd1/Scc1 association with chromatin using chromosome spreads [25].

References