Regulation Of Sister Chromatid Cohesion Research Articles

Mms21 SUMO Ligase Activity Promotes Nucleolar Function in Saccharomyces cerevisiae.

The budding yeast E3 SUMO ligase Mms21, also known as Nse2, is a component of the Smc5/6 complex, which regulates sister chromatid cohesion, DNA replication, and repair. Our study shows that the mms21RINGΔ mutant exhibits (1) reduced ribosomal RNA production; (2) nuclear accumulation of ribosomal proteins; (3) elevated Gcn4 translation, indicating translational stress; and (4) upregulation of Gcn4 targets. Genes involved in ribosome biogenesis and translation are downregulated in the mms21RINGΔ mutant. We identified RPL19A as a novel genetic suppressor of the mms21RINGΔ mutant. Deletion of RPL19A partially suppresses growth defects in both smc5-6 and mms21RINGΔ mutants as well as nuclear accumulation of ribosome subunits in the mms21RINGΔ mutant. Deletion of a previously identified strong suppressor, MPH1, rescues both the accumulation of ribosome subunits and translational stress. This study suggests that the Smc5/6 complex supports nucleolar function.

Abstract 1147: CDCA5 is a novel therapeutic target molecule in oral squamous cell carcinoma

Abstract Molecularly targeted drugs are used in the treatment of a variety of malignant tumors, but this approach to developing novel therapies for oral squamous cell carcinoma (OSCC) has lagged behind the progress seen for other cancers. We attempted to find appropriate molecular targets for OSCC, and identified cell division cycle associated 5 (CDCA5) as a cancer-related gene which was overexpressed in 9 human OSCC cells tested by microarray analysis. CDCA5 was initially identified as a substrate of anaphase-promoting complex and as a regulator of sister chromatid cohesion in HeLa cells. In addition, CDCA5 has been reported to be overexpressed in the majority of human lung cancers and urothelial cancers and to play a critical role in carcinogenesis. However, function of CDCA5 in OSCC remains still unknown. In this study, we investigated the expression and function of CDCA5 in OSCC. First, we confirmed the expression level of CDCA5 in 4 human OSCC cell lines and an immortalized non-neoplastic human keratinocyte cell line, HaCaT, by quantitative RT-PCR (qRT-PCR) and Western blotting. The expression levels of CDCA5 mRNA and protein were markedly elevated in all human OSCC cell lines compared to HaCaT cells. Next, we tested the effect of synthetic small interfering RNAs specific for CDCA5 (siCDCA5) on the growth of human OSCC cells. The RNA interference effect of siCDCA5 was confirmed by Western blotting. Transfection of siCDCA5 suppressed the expression of its target protein in all types of cells. The growth inhibitory effect of siCDCA5 in OSCC cells was evaluated by WST-8 assay. The Knockdown of CDCA5 significantly inhibited the growth of OSCC cells in vitro. Subsequently, we assessed the effect of siCDCA5 on the in vivo growth of human OSCC cells, green fluorescent protein (GFP)-SAS. We administered siCDCA5/atelocollagen complexes into the subcutaneous spaces around the xenograft tumors every 3 days. We found that these complexes significantly reduced the size of subcutaneously xenografted GFP-SAS tumors, compared to the control group treated with synthetic siRNA specific for GFP (siGFP)/atelocollagen complexes. Next, we analyzed the influence of siCDCA5 on the cell cycle of OSCC cells by flow cytometry. Suppression of CDCA5 resulted in the decrease in percentage of cells in G0/G1 phase and the increase in G2 phase. This indicated that the anti-proliferative effect of siCDCA5 was due to G2 arrest. Finally, we investigated the clinical significance of CDCA5 expression in OSCC. We examined the expression of CDCA5 in OSCC tissues by immunohistochemistry, and then found a significant association between CDCA5 expression levels and overall survival. These results suggest that CDCA5 functions as a critical gene supporting OSCC progression and that targeting CDCA5 may be a useful therapeutic strategy for OSCC. Citation Format: Norihiko Tokuzen, Koh-ichi Nakashiro, Hiroshi Tanaka, Kazuki Iwamoto, Hitoshi Akiyama, Hiroyuki Hamakawa. CDCA5 is a novel therapeutic target molecule in oral squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1147.

Involvement of the Cohesin Cofactor PDS5 (SPO76) During Meiosis and DNA Repair in Arabidopsis thaliana.

Maintenance and precise regulation of sister chromatid cohesion is essential for faithful chromosome segregation during mitosis and meiosis. Cohesin cofactors contribute to cohesin dynamics and interact with cohesin complexes during cell cycle. One of these, PDS5, also known as SPO76, is essential during mitosis and meiosis in several organisms and also plays a role in DNA repair. In yeast, the complex Wapl-Pds5 controls cohesion maintenance and colocalizes with cohesin complexes into chromosomes. In Arabidopsis, AtWAPL proteins are essential during meiosis, however, the role of AtPDS5 remains to be ascertained. Here we have isolated mutants for each of the five AtPDS5 genes (A–E) and obtained, after different crosses between them, double, triple, and even quadruple mutants (Atpds5a Atpds5b Atpds5c Atpds5e). Depletion of AtPDS5 proteins has a weak impact on meiosis, but leads to severe effects on development, fertility, somatic homologous recombination (HR) and DNA repair. Furthermore, this cohesin cofactor could be important for the function of the AtSMC5/AtSMC6 complex. Contrarily to its function in other species, our results suggest that AtPDS5 is dispensable during the meiotic division of Arabidopsis, although it plays an important role in DNA repair by HR.

Regulation of sister chromatid cohesion during the mitotic cell cycle.

Orderly execution of two critical events during the cell cycle--DNA replication and chromosome segregation--ensures the stable transmission of genetic materials. The cohesin complex physically connects sister chromatids during DNA replication in a process termed sister chromatid cohesion. Timely establishment and dissolution of sister chromatid cohesion is a prerequisite for accurate chromosome segregation, and is tight regulated by the cell cycle machinery and cohesin-associated proteins. In this review, we discuss recent progress in the molecular understanding of sister chromatid cohesion during the mitotic cell cycle.

Abstract 476: Overexpression and function of CDCA5 in oral squamous cell carcinoma

Abstract Molecular target drugs are used in the treatment of various malignant tumors. However, the development of molecular targeted therapy for oral squamous cell carcinoma (OSCC) is lagging behind other cancers. In this study, we have attempted to identify an appropriate molecular target for treatment of patients with OSCC. We determined the gene expression profiles of human 9 OSCC cell lines and an immortalized non-neoplastic human keratinocyte cell line by microarray analysis, and then found cell division cycle associated 5 (CDCA5) as one of genes which were commonly overexpressed in OSCC cells. CDCA5 was initially identified as substrate of anaphase-promoting complex and as a regulator of sister chromatid cohesion in HeLa. In addition, it has been reported that CDCA5 plays a critical role in human lung carcinogenesis. However, function of CDCA5 in OSCC remains still unknown. First, we confirmed the overexpression of CDCA5 in 5 human OSCC cells by quantitative RT-PCR (qRT-PCR) and Western blotting. The expression levels of CDCA5 mRNA and protein were markedly elevated in all human OSCC cell lines compared to a non-neoplastic human epithelial cell line. Next, we examined the effect of synthetic small interfering RNAs specific for CDCA5 (siCDCA5) on the growth of human OSCC cells. RNAi effect of siCDCA5 was confirmed by Western blotting. Transfection of siCDCA5 suppressed the expression of its target protein in all types of cells. The growth inhibitory effect of siCDCA5 in OSCC cells was evaluated by WST-8 assay. Knockdown of CDCA5 significantly inhibited the growth of OSCC cells in vitro. Subsequently, we analyzed the influence of siCDCA5 on cell cycle by flow cytometry. Suppression of CDCA5 resulted in the decrease in percentage of cells in G0/G1 phase and increase in G2 phase. This indicated that the anti-proliferative effect of siCDCA5 was due to G2 arrest. Furthermore, we investigated the clinical significance of CDCA5 expression in OSCC. The expression of CDCA5 mRNA in tumor and adjacent normal tissues derived from the patient with OSCC was examined by qRT-PCR. Expression levels of CDCA5 mRNA in the OSCC tissues were significantly higher than in normal tissues. We also examined the expression of CDCA5 protein in 80 OSCC cases by immunohistochemistry with anti-CDCA5 antibodies. Tissue expression of CDCA5 was divided into high or low group at 50% stained tumor cells, resulting in 36 cases as high expression and 44 cases as low expression. We then examined the association of CDCA5 expression with various clinicopathological parameters of OSCC patients, and found a significant association between CDCA5 expression levels and pathological staging, metastasis, and recurrence. These results suggest that CDCA5 functions as a critical gene supporting the growth of human OSCC cells and targeting CDCA5 appears a useful therapeutic strategy for the patients with OSCC. Citation Format: Norihiko Tokuzen, Koh-ichi Nakashiro, Hiroshi Tanaka, Yohei Fujita, Kazuki Iwamoto, Hiroyuki Hamakawa. Overexpression and function of CDCA5 in oral squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 476. doi:10.1158/1538-7445.AM2014-476

Abstract 5284: SSU72 functions as a gatekeeper monitoring for chromosome integrity in mammals

Abstract Ssu72 has been initially identified as a protein phosphatase in yeast. It is becoming increasingly clear that Ssu72 plays a major modifier in regulating the transcriptional dynamics through the dephosphorylation (hypophosphorylation) of RNA polymerase II C-terminal domain. Despite these intriguing reports, the physiological function of SSU72 remains unknown particularly in higher eukaryotes. Recently, We have reported that Ssu72 functions as a cohesin-binding phosphatase in regulating sister chromatid cohesion. In addition, we generated the SSU72 conditional knock-out mice, and identified that SSU72 requirement for monitoring hepatic chromosome ploidy and hepatic damage responses in mammals. Furthermore, this study includes the physiology of SSU72 loss-of-function and the novel molecular lesions caused by SSU72 loss in vitro and in vivo. Citation Format: Se-Hyuk Kim, Yoon Jeon, Hyun-Soo Kim, Han-Jeong Lim, Ho Lee, Chang-Woo Lee. SSU72 functions as a gatekeeper monitoring for chromosome integrity in mammals. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5284. doi:10.1158/1538-7445.AM2014-5284

Functional interplay between Aurora B kinase and Ssu72 phosphatase regulates sister chromatid cohesion

Cohesins establish cohesion between replicated sister chromatids and are maintained as a multiprotein complex on chromosome arms until they are phosphorylated by mitotic kinases, such as Aurora B and Plk1. However, the mechanics of how the phosphorylation and dephosphorylation of cohesin subunits by kinases and phosphatases, respectively, leads to the dissociation of the cohesin complex from chromosomes remain unclear. Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. Overexpression of the Aurora B-mediated phosphomimetic mutant of Ssu72 prevents maintainance chromosome arm cohesion. These results provide evidence that Aurora B kinase directly targets Ssu72 phosphatase for regulation of sister chromatid cohesion during early mitosis.

Frequent truncating mutations of STAG2 in bladder cancer.

Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 plays a role in controlling chromosome number but not proliferation of bladder cancer cells. These findings identify STAG2 as among the most commonly mutated genes in bladder cancer discovered to date.

Sister chromatid cohesion defects are associated with chromosome instability in Hodgkin lymphoma cells

BackgroundChromosome instability manifests as an abnormal chromosome complement and is a pathogenic event in cancer. Although a correlation between abnormal chromosome numbers and cancer exist, the underlying mechanisms that cause chromosome instability are poorly understood. Recent data suggests that aberrant sister chromatid cohesion causes chromosome instability and thus contributes to the development of cancer. Cohesion normally functions by tethering nascently synthesized chromatids together to prevent premature segregation and thus chromosome instability. Although the prevalence of aberrant cohesion has been reported for some solid tumors, its prevalence within liquid tumors is unknown. Consequently, the current study was undertaken to evaluate aberrant cohesion within Hodgkin lymphoma, a lymphoid malignancy that frequently exhibits chromosome instability.MethodsUsing established cytogenetic techniques, the prevalence of chromosome instability and aberrant cohesion was examined within mitotic spreads generated from five commonly employed Hodgkin lymphoma cell lines (L-1236, KM-H2, L-428, L-540 and HDLM-2) and a lymphocyte control. Indirect immunofluorescence and Western blot analyses were performed to evaluate the localization and expression of six critical proteins involved in the regulation of sister chromatid cohesion.ResultsWe first confirmed that all five Hodgkin lymphoma cell lines exhibited chromosome instability relative to the lymphocyte control. We then determined that each Hodgkin lymphoma cell line exhibited cohesion defects that were subsequently classified into mild, moderate or severe categories. Surprisingly, ~50% of the mitotic spreads generated from L-540 and HDLM-2 harbored cohesion defects. To gain mechanistic insight into the underlying cause of the aberrant cohesion we examined the localization and expression of six critical proteins involved in cohesion. Although all proteins produced the expected nuclear localization pattern, striking differences in RAD21 expression was observed: RAD21 expression was lowest in L-540 and highest within HDLM-2.ConclusionWe conclude that aberrant cohesion is a common feature of all five Hodgkin lymphoma cell lines evaluated. We further conclude that aberrant RAD21 expression is a strong candidate to underlie aberrant cohesion, chromosome instability and contribute to the development of the disease. Our findings support a growing body of evidence suggesting that cohesion defects and aberrant RAD21 expression are pathogenic events that contribute to tumor development.

Aurora‐A‐elicited Astrin phosphorylation regulates mitotic progression

Astrin is a spindle protein regulating several aspects of mitosis including the maintenance of bipolar spindle pole, regulation of sisterchromatid cohesion and chromosome alignment. However, it remains unclear how to regulate Astrin protein in mitosis. Our present study has shown that Astrin behaves as a mitotic phosphoprotein and was directly phosphorylated by the mitotic kinase Aurora‐A in an in vitro kinase assay. Furthermore, the mitosis dependent phosphorylation of Astrin was blockaded by immunodepletion or shRNA‐mediated knockdown of Aurora‐A. It indicates that Astrin acts as an in vitro and in vivo substrate of Aurora‐A. The phosphorylation site was subsequently mapped to serine 115 of Astrin. And site‐directed mutagenesis analysis revealed that Astrin S115A mutants, no longer serving as a substrate of Aurora‐A, delayed the mitosis progression and induced chromosome misalignment and DNA lagging along the mitotic progression. By contrast, Astrin S115D, which mimics Aurora‐A elicited phosphorylation, accelerated the mitosis progression and slightly deceased the level of DNA lagging. The binding activity of Astrin S115A mutant to its mitotic interaction proteins LC8 and CLASP‐1alpha was remarkably reduced, leading to the mislocalization of the sequential two proteins and the misalignment of chromosome. In conclusion, we are the first to demonstrate that Aurora‐A, a well‐characterized oncokinase controlling a wide range of mitotic events by phosphorylating numerous mitotic factors, phosphorylates Astrin in vitro and in vivo, which guides the binding of Astrin to its cellular partners, and ensures accurate chromosome alignment and segregation and thereby proper mitosis progression.

ASURA (PHB2) Interacts with Scc1 through Chromatin

Sister chromatid cohesion mediated by the cohesin complex is essential for faithful chromosome segregation. Previously we reported that PHB2 (prohibitin2/ASURA), a multifunctional protein, has a role in sister chromatid cohesion. Nevertheless, how ASURA is involved in sister chromatid cohesion still remains unclear. The present co-immunoprecipitation analysis reveals that ASURA interacts with cohesin subunit Scc1 in vivo. We show that ASURA associates with chromatin in a similar manner as Scc1 throughout the cell cycle. Furthermore, our observation using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system indicates that ASURA is important for cohesin maintenance at early mitosis. We have also identified that the conserved PHB domain is responsible for chromatin targeting of ASURA. Our results suggest that the regulation of sister chromatid cohesion is mediated by ASURA binding to chromatin, where ASURA might be involved in cohesin protection through ASURA-Scc1 interactions.

Localization and Regulation of Murine Esco2 During Male and Female Meiosis1

Meiosis is essential for generation of healthy gametes in both sexes and involves recombination and segregation of homologous chromosomes to produce haploid gametes. The initiation of meiosis in both sexes relies upon retinoic acid (RA) (Griswold MD, Hogarth CA, Bowles J, Koopman P. Initiating Meiosis: The Case for Retinoic Acid. Biol Reprod 2012; 86(35):1-7). Previous studies have demonstrated that the stimulated by retinoic acid gene 8 (Stra8) was required for meiotic progression in both the mouse ovary and postnatal testis. To identify additional candidates that may play a role during meiosis, we used microarray databases to generate lists of transcripts with expression profiles similar to that of Stra8 in the embryonic ovary and postnatal testis. One such gene, establishment of cohesion 1 homolog 2 (Saccharomyces cerevisiae) (Esco2), has been described as a regulator of sister chromatid cohesion during mitosis. This study describes the first in-depth analysis of ESCO2 localization and regulation during meiosis in both males and females. ESCO2 colocalized with the gamma H2A histone family member X (H2AFX) in pachytene spermatocytes, indicating that ESCO2 is a component of the XY body. In pachytene cells of the embryonic ovary, ESCO2 colocalized with H2AFX, which is consistent with the presence of ESCO2 in areas of double-stranded breaks. In addition, the expression of Esco2 was found to be regulated by RA in the postnatal testis. These data indicate that ESCO2 may play a vital role in meiosis in both males and females.

Cohesin controls planar cell polarity by regulating the level of the seven‐pass transmembrane cadherin Flamingo

Planar cell polarity (PCP) refers to the coordination of global organ axes and individual cell polarity in vertebrate and invertebrate epithelia. Mechanisms of PCP have been best studied in the Drosophila wing, in which each epidermal cell produces a single wing hair at the distal cell edge, and this spatial specification is mediated by redistribution of the core group proteins, including the seven-pass transmembrane cadherin Flamingo/Starry night (Fmi/Stan), to selective plasma membrane domains. Through genetic screening, we found that a mutation of the SMC3 gene caused dramatic misspecification of wing hair positions. SMC3 protein is one subunit of the cohesin complex, which regulates sister chromatid cohesion and also plays a role in transcriptional control of gene expression. In the SMC3 mutant cells, Fmi appeared to be upregulated by a posttranscriptional mechanism(s), and this elevation of Fmi was at least one cause of the PCP defect. In addition to the PCP phenotype, the loss of the cohesin function affected wing morphogenesis at multiple levels: one malformation was loss of the wing margin, and this was most likely a result of downregulation of the homeodomain protein Cut. At the cellular level, apical cell size and hexagonal packing were affected in the mutant wing. Dysfunction of cohesin in humans results in Cornelia de Lange syndrome (CdLS), which is characterized by various developmental abnormalities and mental retardation. Our analysis of cohesin in epithelia may provide new insight into cellular and molecular mechanisms of CdLS.

A Conserved Motif at the C Terminus of Sororin Is Required for Sister Chromatid Cohesion

Sororin is a positive regulator of sister chromatid cohesion that interacts with the cohesin complex. Sororin is required for the increased stability of the cohesin complex on chromatin following DNA replication and sister chromatid cohesion during G(2). The mechanism by which sororin ensures cohesion is currently unknown. Because the primary sequence of sororin does not contain any previously characterized structural or functional motifs, we have undertaken a structure-function analysis of the sororin protein. Using a series of mutant derivatives of sororin, we show that the ability of sororin to bind to chromatin is separable from both its role in sister chromatid cohesion and its interaction with the cohesin complex. We also show that derivatives of sororin with deletions or mutations in the conserved C terminus fail to rescue the loss-of-cohesion phenotype caused by sororin RNAi and that these mutations also abrogate the association of sororin with the cohesin complex. Our data suggest that the interaction of the highly conserved motif at the C terminus of sororin with the cohesin complex is critical to its ability to mediate sister chromatid cohesion.

RAD21L, a novel cohesin subunit implicated in linking homologous chromosomes in mammalian meiosis

Cohesins are multi-subunit protein complexes that regulate sister chromatid cohesion during mitosis and meiosis. Here we identified a novel kleisin subunit of cohesins, RAD21L, which is conserved among vertebrates. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. This behavior of RAD21L is unique and distinct from that of REC8, another meiosis-specific kleisin subunit. Remarkably, the disappearance of RAD21L at mid pachytene correlates with the completion of DNA double-strand break repair and the formation of crossovers as judged by colabeling with molecular markers, γ-H2AX, MSH4, and MLH1. RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes.

The cohesin-interacting protein, precocious dissociation of sisters 5A/sister chromatid cohesion protein 112, is up-regulated in human astrocytic tumors

Glioblastoma multiforme (GBM) is the most prevalent, highly malignant, invasive and difficult-to-treat primary brain tumor in adults. At the genetic level, it is characterized by a high degree of chromosomal instability and aneuploidy. It has been shown that defects in the mitotic spindle checkpoint could lead to the development of aneuploidy as well as tumorigenesis. Additional proteins regulating sister chromatid cohesion could also be involved in maintaining the fidelity of chromosome segregation. One such protein is the precocious dissociation of sisters 5A (Pds5A), also known as sister chromatid cohesion protein 112. It is a nuclear protein, expressed from the S right through to the mitotic phase. It is highly conserved from yeast to man and plays a role in the establishment, maintenance and dissolution of sister chromatid cohesion. The mutation of Pds5A orthologs in lower organisms results in chromosome missegregation, aneuploidy and DNA repair defects. It is considered that such defects can cause either cell death or contribute to the development of cancer cells. Indeed, altered expression levels of Pds5A have been observed in tumors of the breast, kidney, oesophagus, stomach, liver and colon. Malignant gliomas, however, have not been analysed so far. Herein, we report on the cloning of Rattus norvegicus Pds5A and on the analysis of its expression pattern in rat tissue. We also show that Pds5A is significantly overexpressed at both the mRNA and protein level and that this overexpression correlates positively with the WHO grade of human gliomas. However, functional assays show that the siRNA-mediated knockdown of Pds5A affects sister chromatid cohesion but does not influence mitotic checkpoint function or the proliferation and survival of GBM cells. Although the mechanism by which Pds5A functions in GBM cells remains unclear, its overexpression in high grade gliomas implies that it could play a pivotal role during the development and progression of astrocytic tumors.

RB moonlights in mitosis

Three papers identify a new role for RB1 in regulating sister chromatid cohesion, which suppresses tumorigenesis by preventing chromosome instability

RB moonlights in mitosis

A new role for retinoblastoma in regulating sister chromatid cohesion.

Pds5 is required for homologue pairing and inhibits synapsis of sister chromatids during yeast meiosis

During meiosis, homologues become juxtaposed and synapsed along their entire length. Mutations in the cohesin complex disrupt not only sister chromatid cohesion but also homologue pairing and synaptonemal complex formation. In this study, we report that Pds5, a cohesin-associated protein known to regulate sister chromatid cohesion, is required for homologue pairing and synapsis in budding yeast. Pds5 colocalizes with cohesin along the length of meiotic chromosomes. In the absence of Pds5, the meiotic cohesin subunit Rec8 remains bound to chromosomes with only minor defects in sister chromatid cohesion, but sister chromatids synapse instead of homologues. Double-strand breaks (DSBs) are formed but are not repaired efficiently. In addition, meiotic chromosomes undergo hypercondensation. When the mitotic cohesin subunit Mcd1 is substituted for Rec8 in Pds5-depleted cells, chromosomes still hypercondense, but synapsis of sister chromatids is abolished. These data suggest that Pds5 modulates the Rec8 activity to facilitate chromosome morphological changes required for homologue synapsis, DSB repair, and meiotic chromosome segregation.

Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

BackgroundRoberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to...