Sister chromatid cohesion is essential for chromosome segregation and is mediated by cohesin bound to DNA. Cohesin-DNA interactions can be reversed by the cohesion-associated protein Wapl, whereas a stably DNA-bound form of cohesin is thought to mediate cohesion. In vertebrates, Sororin is essential for cohesion and stable cohesin-DNA interactions, but how Sororin performs these functions is unknown. We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5. In the absence of Wapl, Sororin becomes dispensable for cohesion. We propose that Sororin maintains cohesion by inhibiting Wapl's ability to dissociate cohesin from DNA. Sororin has only been identified in vertebrates, but we show that many invertebrate species contain Sororin-related proteins, and that one of these, Dalmatian, is essential for cohesion in Drosophila. The mechanism we describe here may therefore be widely conserved among different species.

Cohesin is a chromosome-associated multisubunit protein complex that is highly conserved in eukaryotes and has close homologs in bacteria. Cohesin mediates cohesion between replicated sister chromatids and is therefore essential for chromosome segregation in dividing cells. Cohesin is also required for efficient repair of damaged DNA and has important functions in regulating gene expression in both proliferating and post-mitotic cells. Here we discuss how cohesin associates with DNA, how these interactions are controlled during the cell cycle; how binding of cohesin to DNA may mediate sister chromatid cohesion, DNA repair, and gene regulation; and how defects in these processes can lead to human disease.Eukaryotic cells pass their genomes from one cell generation to the next by first replicating their entire nuclear DNA during S phase and then segregating the resulting sister chromatids from each other later during mitosis or meiosis. The segregation step is carried out with the help of the spindle apparatus, which captures replicated chromosomes in a bipolar fashion during prometaphase. In anaphase, the spindle then moves the sister chromatids into opposite directions so that two genetically identical daughter cells can be formed during cytokinesis. This mechanism of chromosome segregation critically depends on the fact that sister chromatids remain physically connected with each other from the time of their synthesis in S phase until they are separated much later in anaphase. Without this cohesion, sister chromatids could be separated from each other before chromosomes were attached to both poles of the spindle, and an equal distribution of sister chromatids into forming daughter cells would not be possible. Identifying the molecular mechanisms of sister chromatid cohesion is therefore of central importance for understanding the cell division cycle of eukaryotic cells.During DNA replication, sister chromatids become automatically intertwined with each other at sites where replication forks collide (Sundin and Varshavsky 1980), and these catenations need to be resolved by topoisomerases before sister chromatids can separate in anaphase (DiNardo et al. 1984). It was therefore initially plausible to assume that cohesion may be mediated by DNA catenation (Murray and Szostak 1985). Catenations can indeed mediate some cohesion between sister chromatids if the activity of topoisomerases is experimentally inhibited (Vagnarelli et al. 2004;Toyoda and Yanagida 2006). However, it is unclear whether catenations are also required for sister chromatid cohesion under physiological conditions; i.e., when topoisomerases are active. For entire chromosomes, it has so far been impossible to address this question, because it is presently not possible to create replicated chromosomes in which sister chromatids are not catenated with each other. However, it is now well established that catenation cannot be sufficient for cohesion, because several proteins have been identified that are essential for cohesion that do not appear to reg...

Sister chromatid cohesion depends on cohesin [1-3]. Cohesin associates with chromatin dynamically throughout interphase [4]. During DNA replication, cohesin establishes cohesion [5], and this process coincides with the generation of a cohesin subpopulation that is more stably bound to chromatin [4]. In mitosis, cohesin is removed from chromosomes, enabling sister chromatid separation [6]. How cohesin associates with chromatin and establishes cohesion is poorly understood. By searching for proteins that are associated with chromatin-bound cohesin, we have identified sororin, a protein that was known to be required for cohesion [7]. To obtain further insight into sororin's function, we have addressed when during the cell cycle sororin is required for cohesion. We show that sororin is dispensable for the association of cohesin with chromatin but that sororin is essential for proper cohesion during G2 phase. Like cohesin, sororin is also needed for efficient repair of DNA double-strand breaks in G2. Finally, sororin is required for the presence of normal amounts of the stably chromatin-bound cohesin population in G2. Our data indicate that sororin interacts with chromatin-bound cohesin and functions during the establishment or maintenance of cohesion in S or G2 phase, respectively.

A recent surge of studies have suggested that many novel genes arise de novo from previously noncoding DNA and not by duplication. However, most studies concentrated on longer evolutionary time scales and rarely considered protein structural properties. Therefore, it remains unclear how these properties are shaped by evolution, depend on genetic mechanisms and influence gene survival. Here we compare open reading frames (ORFs) from high coverage transcriptomes from mouse and another four mammals covering 160 million years of evolution. We find that novel ORFs pervasively emerge from noncoding regions but are rapidly lost again, while relatively fewer arise from the divergence of coding sequences but are retained much longer. We also find that a subset (14%) of the mouse-specific ORFs bind ribosomes and are potentially translated, showing that such ORFs can be the starting points of gene emergence. Surprisingly, disorder and other protein properties of young ORFs hardly change with gene age in short time frames. Only length and nucleotide composition change significantly. Thus, some transcribed de novo genes resemble 'frozen accidents' of randomly emerged ORFs that survived initial purging. This perspective complies with very recent studies indicating that some neutrally evolving transcripts containing random protein sequences may be translated and be viable starting points of de novo gene emergence.

Orphan genes, lacking detectable homologs in outgroup species, typically represent 10-30% of eukaryotic genomes. Efforts to find the source of these young genes indicate that de novo emergence from non-coding DNA may in part explain their prevalence. Here, we investigate the roots of orphan gene emergence in the Drosophila genus. Across the annotated proteomes of twelve species, we find 6297 orphan genes within 4953 taxon-specific clusters of orthologs. By inferring the ancestral DNA as non-coding for between 550 and 2467 (8.7-39.2%) of these genes, we describe for the first time how de novo emergence contributes to the abundance of clade-specific Drosophila genes. In support of them having functional roles, we show that de novo genes have robust expression and translational support. However, the distinct nucleotide sequences of de novo genes, which have characteristics intermediate between intergenic regions and conserved genes, reflect their recent birth from non-coding DNA. We find that de novo genes encode more disordered proteins than both older genes and intergenic regions. Together, our results suggest that gene emergence from non-coding DNA provides an abundant source of material for the evolution of new proteins. Following gene birth, gradual evolution over large evolutionary timescales moulds sequence properties towards those of conserved genes, resulting in a continuum of properties whose starting points depend on the nucleotide sequences of an initial pool of novel genes.