bims-ginsta 2023-08-27 papers

bioRxiv. 2023 Aug 07. pii: 2023.08.06.552174. [Epub ahead of print]

An Aurora kinase A-BOD1L1-PP2A B56 Axis promotes chromosome segregation fidelity.

Thomas J Kucharski, Irma M Vlasac, Martin R Higgs, Brock C Christensen, Duane A Compton.

Cancer cells are often aneuploid and frequently display elevated rates of chromosome mis-segregation in a phenomenon called chromosomal instability (CIN). CIN is commonly caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduces the efficiency of correction of erroneous K-MT attachments. We recently showed that UMK57, a chemical agonist of MCAK (alias KIF2C), improves chromosome segregation fidelity in CIN cancer cells but that cells rapidly develop resistance to UMK57. To determine the mechanism of resistance we performed unbiased proteomic screens which revealed increased phosphorylation in cells adapted to UMK57 at two Aurora kinase A phosphoacceptor sites on BOD1L1 (alias FAM44A). BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57 in CIN cancer cells. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression, and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with low doses of taxol or Aurora kinase A inhibitor. Thus, an Aurora kinase A -BOD1L1-PP2A axis promotes faithful chromosome segregation during mitosis.

DOI: https://doi.org/10.1101/2023.08.06.552174

Curr Opin Genet Dev. 2023 Aug 17. pii: S0959-437X(23)00076-X. [Epub ahead of print]82 102096

Modeling X-chromosome inactivation and reactivation during human development.

Shafqat A Khan, Thorold W Theunissen.

Stem-cell-based embryo models generate much excitement as they offer a window into an early phase of human development that has remained largely inaccessible to scientific investigation. An important epigenetic phenomenon during early embryogenesis is the epigenetic silencing of one of the two X chromosomes in female embryos, which ensures an equal output of X-linked gene expression between the sexes. X-chromosome inactivation (XCI) is thought to be established within the first three weeks of human development, although the inactive X-chromosome is reactivated in primordial germ cells (PGCs) that migrate to the embryonic gonads. Here, we summarize our current understanding of X-chromosome dynamics during human development and comment on the potential of recently established stem-cell-based models to reveal the underlying mechanisms.

DOI: https://doi.org/10.1016/j.gde.2023.102096

Chromosome Res. 2023 Aug 25. 31(3): 24

Consequences of gaining an extra chromosome.

Eduardo M Torres.

Mistakes in chromosome segregation leading to aneuploidy are the primary cause of miscarriages in humans. Excluding sex chromosomes, viable aneuploidies in humans include trisomies of chromosomes 21, 18, or 13, which cause Down, Edwards, or Patau syndromes, respectively. While individuals with trisomy 18 or 13 die soon after birth, people with Down syndrome live to adulthood but have intellectual disabilities and are prone to multiple diseases. At the cellular level, mistakes in the segregation of a single chromosome leading to a cell losing a chromosome are lethal. In contrast, the cell that gains a chromosome can survive. Several studies support the hypothesis that gaining an extra copy of a chromosome causes gene-specific phenotypes and phenotypes independent of the identity of the genes encoded within that chromosome. The latter, referred to as aneuploidy-associated phenotypes, are the focus of this review. Among the conserved aneuploidy-associated phenotypes observed in yeast and human cells are lower viability, increased gene expression, increased protein synthesis and turnover, abnormal nuclear morphology, and altered metabolism. Notably, abnormal nuclear morphology of aneuploid cells is associated with increased metabolic demand for de novo synthesis of sphingolipids. These findings reveal important insights into the possible pathological role of aneuploidy in Down syndrome. Despite the adverse effects on cell physiology, aneuploidy is a hallmark of cancer cells. Understanding how aneuploidy affects cell physiology can reveal insights into the selective pressure that aneuploid cancer cells must overcome to support unlimited proliferation.

Keywords: Aneuploidy; Down syndrome; Human trisomy; Nuclear morphology; Serine synthesis; Sphingolipids; Yeast

DOI: https://doi.org/10.1007/s10577-023-09732-w

Nat Commun. 2023 Aug 21. 14(1): 5071

TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells.

Shaun Scaramuzza, Rebecca M Jones, Martina Muste Sadurni, Alicja Reynolds-Winczura, Divyasree Poovathumkadavil, Abigail Farrell, Toyoaki Natsume, Patricia Rojas, Cyntia Fernandez Cuesta, Masato T Kanemaki, Marco Saponaro, Agnieszka Gambus.

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.

DOI: https://doi.org/10.1038/s41467-023-40695-y

Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2301457120

Phase separation of +TIP networks regulates microtubule dynamics.

Julie Miesch, Robert T Wimbish, Marie-Claire Velluz, Charlotte Aumeier.

Regulation of microtubule dynamics is essential for diverse cellular functions, and proteins that bind to dynamic microtubule ends can regulate network dynamics. Here, we show that two conserved microtubule end-binding proteins, CLIP-170 and EB3, undergo phase separation and form dense liquid networks. When CLIP-170 and EB3 act together, the multivalency of the network increases, which synergistically increases the amount of protein in the dense phase. In vitro and in cells, these liquid networks can concentrate tubulin. In vitro, in the presence of microtubules, phase separation of EB3/CLIP-170 can enrich tubulin all along the microtubule. In this condition, microtubule growth speed increases up to twofold and the frequency of depolymerization events are strongly reduced compared to conditions in which there is no phase separation. Our data show that phase separation of EB3/CLIP-170 adds an additional layer of regulation to the control of microtubule growth dynamics.

Keywords: CLIP-170; EB3; liquid–liquid phase separation; microtubule; tubulin condensation

DOI: https://doi.org/10.1073/pnas.2301457120