Absence of the spindle assembly checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion

The fidelity of mitosis depends on cohesive forces that keep sister chromatids together. This is mediated by cohesin that embraces sister chromatid fibers from the time of their replication until the subsequent mitosis [1-3]. Cleavage of cohesin marks anaphase onset, where single chromatids are dragged to the poles by the mitotic spindle [4-6]. Cohesin cleavage should only occur when all chromosomes are properly bio-oriented to ensure equal genome distribution and prevent random chromosome segregation. Unscheduled loss of sister chromatid cohesion is prevented by a safeguard mechanism known as the spindle assembly checkpoint (SAC) [7, 8]. To identify specific conditions capable of restoring defects associated with cohesion loss, we screened for genes whose depletion modulates Drosophila wing development when sister chromatid cohesion is impaired. Cohesion deficiency was induced by knockdown of the acetyltransferase separation anxiety (San)/Naa50, a cohesin complex stabilizer [9-12]. Several genes whose function impacts wing development upon cohesion loss were identified. Surprisingly, knockdown of key SAC proteins, Mad2 and Mpsl, suppressed developmental defects associated with San depletion. SAC impairment upon cohesin removal, triggered by San depletion or artificial removal of the cohesin complex, prevented extensive genome shuffling, reduced segregation defects, and restored cell survival. This counterintuitive phenotypic suppression was caused by an intrinsic bias for efficient chromosome biorientation at mitotic entry, coupled with slow engagement of error-correction reactions. Thus, in contrast to SAC's role as a safeguard mechanism for mitotic fidelity, removal of this checkpoint alleviates mitotic errors when sister chromatid cohesion is compromised.Lisboa Regional Operational Programme (Lisboa 2020) through the European Regional Development Fund (FEDER); Fundacao para a Ciencia e a Tecnologia (FCT; Portugal); FCT [SFRH/BPD/87482/2012, SFRH /BD/52438/2013, PD/BD/52428/2013, PD/00117/2012, CRM: 0027030, PTDC/BEX-BID/0395/2014, UID/BIM/04773/2013 CBMR 1334, IF/00851/2012/CP0185/CT0004]; Association for International Cancer Research [AICR 10-0553]; EMBO Installation Grant [IG2778]; European Research Council Starting Grant [ERC-2014-STG-638917]; [PPBI-POCI-01-0145-FEDER-022122]; [LISBOA-01-0145-FEDER-022170

A dual-function SNF2 protein drives chromatid resolution and nascent transcripts removal in mitosis

Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription in Drosophila early embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to the eviction of nascent transcripts, we uncover that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that the removal of nascent transcripts upon mitotic entry is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.info:eu-repo/semantics/publishedVersio

Evolution of GnRH ligands and receptors in gnathostomata

Gonadotropin-releasing hormone (GnRH) is the final common signaling molecule used by the brain to regulate reproduction in all vertebrates. Until now, a total of 24 GnRH structural variants have been characterized from vertebrate, protochordate and invertebrate nervous tissue. Almost all vertebrates already investigated have at least two GnRH forms coexisting in the central nervous system. Furthermore, it is now well accepted that three GnRH forms are present both in early and late evolved teleostean fishes. The number and taxonomic distribution of the different GnRH variants also raise questions about the phylogenetic relationships between them. Most of the GnRH phylogenetic analyses are in agreement with the widely accepted idea that the GnRH family can be divided into three main groups. However, the examination of the gnathostome GnRH phylogenetic relationships clearly shows the existence of two main paralogous GnRH lineages: the ‘‘midbrain GnRH” group and the “forebrain GnRH” group. The first one, represented by chicken GnRH-II forms, and the second one composed of two paralogous lineages, the salmon GnRH cluster (only represented in teleostean fish species) and the hypophysotropic GnRH cluster, also present in tetrapods. This analysis suggests that the two forebrain clades share a common precursor and reinforces the idea that the salmon GnRH branch has originated from a duplication of the hypophysotropic lineage. GnRH ligands exert their activity through G protein-coupled receptors of the rhodopsin-like family. As with the ligands, multiple GnRHRs are expressed in individual vertebrate species and phylogenetic analyses have revealed that all vertebrate GnRHRs cluster into three main receptor types. However, new data and a new phylogenetic analysis propose a two GnRHR type model, in which different rounds of gene duplications may have occurred in different groups within each lineage

Induced aneuploidy in neural stem cells triggers a delayed stress response and impairs adult life span in flies.

Studying aneuploidy during organism development has strong limitations because chronic mitotic perturbations used to generate aneuploidy usually result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time-controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity. Larvae challenged with aneuploidy hatch into adults with severe motor defects shortening their life span. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, a complex array of karyotypes, and cellular abnormalities. Notably, when other brain-cell lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed. Protecting only the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult life span, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy