Disease relevance of MCD1

• Failure of sister chromatid cohesion results in the aneuploidy characteristic of many birth defects and tumors in humans [1].

High impact information on MCD1

• Proper separation of homologous chromosomes at the first meiotic division requires the production of physical connections (chiasmata) between homologs through recombinational exchange of chromosome arms after sister-chromatid cohesion is established but before chromosome segregation takes place [2].
• Instead, we found a significant decrease in the association of cohesin subunit Mcd1p (Scc1p) to rDNA in sir2Delta relative to SIR2 strains [3].
• The cohesin complex is essential for sister chromatid cohesion during mitosis [4].
• Separin immunoprecipitates are sufficient to cleave SCC1, indicating that separin is associated with a protease activity [5].
• We show that residual amounts of the cohesin SCC1 remain associated with human centromeres until the onset of anaphase when a similarly small amount of SCC1 is cleaved [5].

Biological context of MCD1

• Disruption and functional analysis of seven ORFs on chromosome IV: YDL057w, YDL012c, YDL010w, YDL009c, YDL008w (APC11), YDL005c (MED2) and YDL003w (MCD1) [6].
• YDL003w (also termed MCD1) is a homologue of Schizosaccharomyces pombe rad21, an essential gene implicated in DNA double-strand break repair and nuclear organization in fission yeast [6].
• These results suggest that SCC1/MCD1/RHC21 is negatively regulated by the PKA pathway via the anaphase promoting complex (APC) [7].
• Cohesion between sister chromatids during G2 and M phases depends on the "cohesin" protein Scc1p (Mcd1p) [8].
• By looking for mutants that separate sister centromeres in the presence of Pds1p, this and a previous study have identified six proteins essential for establishing or maintaining sister chromatid cohesion [9].

Anatomical context of MCD1

• Cohesin therefore has a central role in generating a dynamic tension between microtubules and sister chromatid cohesion at centromeres, which lasts until chromosome segregation is finally promoted by separin-dependent cleavage of the cohesin subunit Scc1p [10].
• Destruction of sister chromatid cohesion by Separase may be a universal feature of mitosis in eukaryotic cells [11].
• During meiosis, sequential release of sister chromatid cohesion (SSC) during two successive nuclear divisions allows the production of haploid gametes from diploid progenitor cells [12].
• Here, we provide the first evidence that the nuclear envelope spindle pole body assembly component Mps3p performs a function critical to sister chromatid cohesion [13].
• The sister-chromatid cohesion protein ORD is required for chiasma maintenance in Drosophila oocytes [14].

Associations of MCD1 with chemical compounds

• In the budding yeast Saccharomyces cerevisiae loss of sister chromatid cohesion depends on a separating protein (separin) called Esp1 [15].
• A ubiquitin ligase, the anaphase-promoting complex (APC), controls events in chromosome metabolism such as sister chromatid cohesion and may regulate H3 phosphorylation by targeting Aurora A, one of several S10-directed H3 kinases in vertebrate cells, for destruction by the proteasome [16].
• Securin(-/-)separase(+/S1121A) cells are viable but fail to maintain sister chromatid cohesion in response to the disruption of spindle microtubules, show enhanced sensitivity to nocodazole, and cannot recover from prometaphase arrest [17].
• The mechanism by which cohesin binds to DNA, and how sister chromatid cohesion is established, is unknown [18].
• Interestingly, in the fission yeast Schizosaccharomyces pombe, the eso1(+) encoded protein is comprised of two domains, wherein the NH(2) terminus is highly homologous to Poleta, and the COOH terminus is highly homologous to the S. cerevisiae Ctf7 protein which is essential for the establishment of sister chromatid cohesion during S phase [19].

Physical interactions of MCD1

• Pds5p and the cohesin complex are required for sister chromatid cohesion and localize to the same chromosomal loci over the same cell cycle window [20].
• The Trf4p/Pol sigma DNA polymerase (formerly Trf4p/Pol kappa) couples DNA replication to the establishment of sister chromatid cohesion [21].
• Ctf8p is a component of Ctf18-RFC, an alternative replication factor C-like complex required for efficient sister chromatid cohesion in Saccharomyces cerevisiae [22].

Enzymatic interactions of MCD1

• Several recent reports show that the protease Esp1 cleaves the cohesin subunit Scc1/Mcd1 to induce sister-chromatid segregation in yeast and vertebrates [23].

Regulatory relationships of MCD1

• Pds5p regulates the maintenance of sister chromatid cohesion and is sumoylated to promote the dissolution of cohesion [20].
• These data indicate that separase function is not restricted to anaphase initiation and that its role in promoting loss of sister chromatid cohesion might be preferentially at arms but not centromeres [24].

Other interactions of MCD1

• Furthermore, Pds5p localization to chromosomes is dependent on Mcd1p [25].
• Sister chromatid cohesion is resolved at anaphase onset when separase, a site-specific protease, cleaves the Scc1 subunit of the chromosomal cohesin complex that is responsible for holding sister chromatids together [26].
• In scc-3 mutant animals, normal SCs were not visible and approximately 24 DAPI-positive structures were seen at diakinesis, indicating that SCC-3 is necessary for sister chromatid cohesion [27].
• CTF7/ECO1 is an essential yeast gene required for the establishment of sister chromatid cohesion [28].
• We also show that trf5 Delta mutants, like trf4 Delta mutants, are defective in DNA repair and sister chromatid cohesion [29].

Analytical, diagnostic and therapeutic context of MCD1

• Sister chromatid cohesion is mediated by evolutionary conserved chromosomal proteins, termed "cohesins." Using an extension of chromatin immunoprecipitation, we have analyzed the distribution of cohesins Mcd1/ Sccl and Smc1 along yeast chromosome III [30].
• 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 [31].
• Pds1 and Mcd1/Scc1 stability is measured in populations by Western blots [31].

References