Abstract
Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development and their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machinery — for example, the development of molecular glues and PROTACs — might facilitate clinical therapy.
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References
Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).
Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).
Clague, M. J., Urbe, S. & Komander, D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat. Rev. Mol. Cell Biol. 20, 338–352 (2019).
Pinto-Fernandez, A. et al. Comprehensive landscape of active deubiquitinating enzymes profiled by advanced chemoproteomics. Front. Chem. 7, 592 (2019).
Wrana, J. L. Signaling by the TGFβ superfamily. Cold Spring Harb. Perspect. Biol. 5, a011197 (2013).
Jiang, J. & Hui, C. C. Hedgehog signaling in development and cancer. Dev. Cell 15, 801–812 (2008).
Steinhart, Z. & Angers, S. Wnt signaling in development and tissue homeostasis. Development 145, 146589 (2018).
Lim, S. & Kaldis, P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 140, 3079–3093 (2013).
Gouti, M. et al. A gene regulatory network balances neural and mesoderm specification during vertebrate trunk development. Dev. Cell 41, 243–261.e7 (2017).
Deng, L., Meng, T., Chen, L., Wei, W. & Wang, P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct. Target. Ther. 5, 11 (2020).
Werner, A., Manford, A. G. & Rape, M. Ubiquitin-dependent regulation of stem cell biology. Trends. Cell Biol. 27, 568–579 (2017).
Liu, L. et al. UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinforma (Oxford, England) 35, 2882–2884 (2019).
Baek, K. et al. NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly. Nature 578, 461–466 (2020).
Berndsen, C. E. & Wolberger, C. New insights into ubiquitin E3 ligase mechanism. Nat. Struct. Mol. Biol. 21, 301–307 (2014).
Pao, K. C. et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556, 381–385 (2018).
Mabbitt, P. D. et al. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. Nat. Chem. Biol. 16, 1227–1236 (2020).
Joazeiro, C. A. P. Mechanisms and functions of ribosome-associated protein quality control. Nat. Rev. Mol. Cell. Biol. 20, 368–383 (2019).
Thrun, A. et al. Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing. Mol. Cell 81, 2112–2122.e7 (2021).
Mizushima, T. et al. Structural basis for the selection of glycosylated substrates by SCF(Fbs1) ubiquitin ligase. Proc. Natl Acad. Sci. USA 104, 5777–5781 (2007).
Horn-Ghetko, D. et al. Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly. Nature 590, 671–676 (2021).
Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016).
French, M. E., Koehler, C. F. & Hunter, T. Emerging functions of branched ubiquitin chains. Cell Discov. 7, 6 (2021).
Ohtake, F., Saeki, Y., Ishido, S., Kanno, J. & Tanaka, K. The K48–K63 branched ubiquitin chain regulates NF-κB signaling. Mol. Cell 64, 251–266 (2016).
Akutsu, M., Dikic, I. & Bremm, A. Ubiquitin chain diversity at a glance. J. Cell Sci. 129, 875–880 (2016).
Ohtake, F., Tsuchiya, H., Saeki, Y. & Tanaka, K. K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains. Proc. Natl Acad. Sci. USA 115, E1401–E1408 (2018).
Meyer, H. J. & Rape, M. Enhanced protein degradation by branched ubiquitin chains. Cell 157, 910–921 (2014).
Luis Villanueva-Cañas, J. et al. New genes and functional innovation in mammals. Genome Biol. Evol. 9, 1886–1900 (2017).
Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M. & Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15, 737–746 (2019).
Vittal, V., Stewart, M. D., Brzovic, P. S. & Klevit, R. E. Regulating the regulators: recent revelations in the control of E3 ubiquitin ligases. J. Biol. Chem. 290, 21244–21251 (2015).
Song, L. & Luo, Z. Q. Post-translational regulation of ubiquitin signaling. J. Cell Biol. 218, 1776–1786 (2019).
Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA 98, 11598–11603 (2001).
Nihira, N. T. et al. Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function. Sci. Signal. 10, aai8026 (2017).
Miyauchi, Y., Yogosawa, S., Honda, R., Nishida, T. & Yasuda, H. Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes. J. Biol. Chem. 277, 50131–50136 (2002).
Gu, L. et al. Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell 30, 623–636 (2016).
Liu, X. et al. NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2. EMBO Rep. 17, 349–366 (2016).
Zhao, K. et al. Regulation of the Mdm2–p53 pathway by the ubiquitin E3 ligase MARCH7. EMBO Rep. 19, 305–319 (2018).
Bai, J. et al. SCF(FBXO22) targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis. Proc. Natl Acad. Sci. USA 116, 11754–11763 (2019).
Carr, M. I., Roderick, J. E., Gannon, H. S., Kelliher, M. A. & Jones, S. N. Mdm2 phosphorylation regulates its stability and has contrasting effects on oncogene and radiation-induced tumorigenesis. Cell Rep. 16, 2618–2629 (2016).
Cetkovská, K., Šustová, H. & Uldrijan, S. Ubiquitin-specific peptidase 48 regulates Mdm2 protein levels independent of its deubiquitinase activity. Sci. Rep. 7, 43180 (2017).
Basar, M. A., Beck, D. B. & Werner, A. Deubiquitylases in developmental ubiquitin signaling and congenital diseases. Cell Death Differ. 28, 538–556 (2021).
Dou, H. et al. Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nat. Struct. Mol. Biol. 19, 184–192 (2012).
Wang, J. et al. Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition. J. Biol. Chem. 285, 12279–12288 (2010).
Plechanovova, A. et al. Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nat. Struct. Mol. Biol. 18, 1052–1059 (2011).
Zheng, N. & Shabek, N. Ubiquitin ligases: structure, function, and regulation. Annu. Rev. Biochem. 86, 129–157 (2017).
Ossareh-Nazari, B. et al. Ubiquitylation by the Ltn1 E3 ligase protects 60S ribosomes from starvation-induced selective autophagy. J. Cell Biol. 204, 909–917 (2014).
Dealy, M. J. et al. Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E. Nat. Genet. 23, 245–248 (1999).
Singer, J. D., Gurian-West, M., Clurman, B. & Roberts, J. M. Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev. 13, 2375–2387 (1999).
Jiang, B. et al. Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development. PLoS ONE 7, e37070 (2012).
Chu, J. et al. A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration. Proc. Natl Acad. Sci. USA 106, 2097–2103 (2009).
Fukami, M. et al. Catastrophic cellular events leading to complex chromosomal rearrangements in the germline. Clin. Genet. 91, 653–660 (2017).
Zitzmann, M. & Rohayem, J. Gonadal dysfunction and beyond: clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome. Am. J. Med. Genet. C. Semin. Med. Genet. 184, 302–312 (2020).
Hattori, A. & Fukami, M. Established and novel mechanisms leading to de novo genomic rearrangements in the human germline. Cytogenet Genome Res. 160, 167–176 (2020).
Baska, K. M. et al. Mechanism of extracellular ubiquitination in the mammalian epididymis. J. Cell Physiol. 215, 684–696 (2008).
Kanatsu-Shinohara, M., Onoyama, I., Nakayama, K. I. & Shinohara, T. Skp1–Cullin–F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal. Proc. Natl Acad. Sci. USA 111, 8826–8831 (2014).
Griswold, M. D. Spermatogenesis: the commitment to meiosis. Physiol. Rev. 96, 1–17 (2016).
Ji, S. et al. Bam-dependent deubiquitinase complex can disrupt germ-line stem cell maintenance by targeting cyclin A. Proc. Natl Acad. Sci. USA 114, 6316–6321 (2017).
Tian, Q., Guo, S. M., Xie, S. M., Yin, Y. & Zhou, L. Q. Rybp orchestrates spermatogenesis via regulating meiosis and sperm motility in mice. Cell Cycle 19, 1492–1501 (2020).
Hasegawa, K. et al. SCML2 establishes the male germline epigenome through regulation of histone H2A ubiquitination. Dev. Cell 32, 574–588 (2015).
Zhang, J. et al. Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing. Cell Death Differ. 26, 1251–1266 (2019).
Zhang, J. et al. The CRL4–DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation. Cell Mol. Life Sci. 77, 2181–2197 (2020).
Alqwaifly, M. & Bohlega, S. Ataxia and hypogonadotropic hypogonadism with intrafamilial variability caused by RNF216 mutation. Neurol. Int. 8, 6444 (2016).
Bustos, F. et al. RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation. Cell Rep. 23, 1599–1611 (2018).
Frints, S. G. M. et al. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Mol. Psychiatry 24, 1748–1768 (2019).
Margolin, D. H. et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N. Engl. J. Med. 368, 1992–2003 (2013).
Melnick, A. F. et al. RNF216 is essential for spermatogenesis and male fertilitydagger. Biol. Reprod. 100, 1132–1134 (2019).
Seenivasan, R. et al. Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome. Hum. Mol. Genet. 28, 2862–2873 (2019).
Geng, Y. et al. Kinase-independent function of cyclin E. Mol. Cell 25, 127–139 (2007).
Geng, Y. et al. Cyclin E ablation in the mouse. Cell 114, 431–443 (2003).
Atchison, F. W. & Means, A. R. Spermatogonial depletion in adult Pin1-deficient mice. Biol. Reprod. 69, 1989–1997 (2003).
Koepp, D. M. et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 294, 173–177 (2001).
Reavie, L. et al. Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase–substrate complex. Nat. Immunol. 11, 207–215 (2010).
Tetzlaff, M. T. et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc. Natl Acad. Sci. USA 101, 3338–3345 (2004).
Iyengar, P. V., Hirota, T., Hirose, S. & Nakamura, N. Membrane-associated RING-CH 10 (MARCH10 protein) is a microtubule-associated E3 ubiquitin ligase of the spermatid flagella. J. Biol. Chem. 286, 39082–39090 (2011).
Lin, C. Y. et al. Human X-linked intellectual disability factor CUL4B is required for post-meiotic sperm development and male fertility. Sci. Rep. 6, 20227 (2016).
Yin, Y. et al. Cell autonomous and nonautonomous function of CUL4B in mouse spermatogenesis. J. Biol. Chem. 291, 6923–6935 (2016).
Zhao, B., Ito, K., Iyengar, P. V., Hirose, S. & Nakamura, N. MARCH7 E3 ubiquitin ligase is highly expressed in developing spermatids of rats and its possible involvement in head and tail formation. Histochem. Cell Biol. 139, 447–460 (2013).
Isidor, B., Pichon, O., Baron, S., David, A. & Le Caignec, C. Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia. Am. J. Med. Genet. A 152A, 175–180 (2010).
Kerzendorfer, C. et al. CUL4B-deficiency in humans: understanding the clinical consequences of impaired Cullin 4–RING E3 ubiquitin ligase function. Mech. Ageing Dev. 132, 366–373 (2011).
Tarpey, P. S. et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am. J. Hum. Genet. 80, 345–352 (2007).
Zou, Y. et al. Mutation in CUL4B, which encodes a member of cullin–RING ubiquitin ligase complex, causes X-linked mental retardation. Am. J. Hum. Genet. 80, 561–566 (2007).
Flores, D., Madhavan, M., Wright, S. & Arora, R. Mechanical and signaling mechanisms that guide pre-implantation embryo movement. Development 147, 193490 (2020).
Flach, G., Johnson, M. H., Braude, P. R., Taylor, R. A. & Bolton, V. N. The transition from maternal to embryonic control in the 2-cell mouse embryo. EMBO J. 1, 681–686 (1982).
Tadros, W. & Lipshitz, H. D. The maternal-to-zygotic transition: a play in two acts. Development 136, 3033–3042 (2009).
Toralova, T., Kinterova, V., Chmelikova, E. & Kanka, J. The neglected part of early embryonic development: maternal protein degradation. Cell Mol. Life Sci. 77, 3177–3194 (2020).
Sha, Q. Q., Zhang, J. & Fan, H. Y. A story of birth and death: mRNA translation and clearance at the onset of maternal-to-zygotic transition in mammalsdagger. Biol. Reprod. 101, 579–590 (2019).
Zhang, Y. L. et al. DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development. EMBO J. 37, e98981 (2018).
Liu, Y., Zhao, L. W., Shen, J. L., Fan, H. Y. & Jin, Y. Maternal DCAF13 regulates chromatin tightness to contribute to embryonic development. Sci. Rep. 9, 6278 (2019).
Zhang, Q. et al. CUL1 promotes trophoblast cell invasion at the maternal–fetal interface. Cell Death Dis. 4, e502 (2013).
Sun, X. et al. Abnormal Cullin1 neddylation-mediated p21 accumulation participates in the pathogenesis of recurrent spontaneous abortion by regulating trophoblast cell proliferation and differentiation. Mol. Hum. Reprod. 26, 327–339 (2020).
Wang, P. et al. Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development. J. Clin. Invest. 129, 4393–4407 (2019).
Tan, D., Liang, H., Cao, K., Yi, Q. & Zhang, Q. CUL4A enhances human trophoblast migration and is associated with pre-eclampsia. Int. J. Clin. Exp. Pathol. 10, 10544–10551 (2017).
Wu, L., Liu, Q., Fan, C., Yi, X. & Cheng, B. MALAT1 recruited the E3 ubiquitin ligase FBXW7 to induce CRY2 ubiquitin-mediated degradation and participated in trophoblast migration and invasion. J. Cell Physiol. 236, 2169–2177 (2021).
Yang, Q. et al. Smurf2 participates in human trophoblast cell invasion by inhibiting TGF-β type I receptor. J. Histochem. Cytochem. 57, 605–612 (2009).
Wu, L., Cheng, B., Liu, Q., Jiang, P. & Yang, J. CRY2 suppresses trophoblast migration and invasion in recurrent spontaneous abortion. J. Biochem. 167, 79–87 (2020).
Kandasamy, V. et al. A study on the incidence of neural tube defects in a tertiary care hospital over a period of five years. J. Clin. Diagn. Res. 9, QC01–QC04 (2015).
Maksimova, N. et al. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. J. Med. Genet. 44, 772–778 (2007).
Clayton, P. E. et al. Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination. Clin. Endocrinol. 77, 335–342 (2012).
Takatani, T., Shiohama, T., Takatani, R. & Shimojo, N. A novel CUL7 mutation in a Japanese patient with 3M syndrome. Hum. Genome Var. 5, 30 (2018).
Hu, L. et al. Identification of two CUL7 variants in two Chinese families with 3-M syndrome by whole-exome sequencing. J. Clin. Lab. Anal. 34, e23265 (2020).
Dupont, S. et al. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell 121, 87–99 (2005).
Werner, J. M. et al. Hallmarks of primary neurulation are conserved in the zebrafish forebrain. Commun. Biol. 4, 147 (2021).
Ferrer-Vaquer, A. & Hadjantonakis, A. K. Birth defects associated with perturbations in preimplantation, gastrulation, and axis extension: from conjoined twinning to caudal dysgenesis. Wiley Interdiscip. Rev. Dev. Biol. 2, 427–442 (2013).
Greene, N. D. & Copp, A. J. Neural tube defects. Annu. Rev. Neurosci. 37, 221–242 (2014).
Liu, L. et al. Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis. Cell Res. 22, 1258–1269 (2012).
Rolfo, A., Garcia, J., Todros, T., Post, M. & Caniggia, I. The double life of MULE in preeclamptic and IUGR placentae. Cell Death Dis. 3, e305 (2012).
Sarkar, A. A. et al. Hectd1 is required for development of the junctional zone of the placenta. Dev. Biol. 392, 368–380 (2014).
Sarkar, A. A., Sabatino, J. A., Sugrue, K. F. & Zohn, I. E. Abnormal labyrinthine zone in the Hectd1-null placenta. Placenta 38, 16–23 (2016).
Nicholson, L. K. Mechanism of midline defect-causing mutation P151L in MID1 revealed. FEBS J. 284, 2167–2169 (2017).
Trockenbacher, A. et al. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat. Genet. 29, 287–294 (2001).
Wright, K. M., Du, H. & Massiah, M. A. Structural and functional observations of the P151L MID1 mutation reveal alpha4 plays a significant role in X-linked Opitz syndrome. FEBS J. 284, 2183–2193 (2017).
Buiting, K., Williams, C. & Horsthemke, B. Angelman syndrome — insights into a rare neurogenetic disorder. Nat. Rev. Neurol. 12, 584–593 (2016).
Wang, J. et al. UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology. Proc. Natl Acad. Sci. USA 116, 12500–12505 (2019).
Wlodarchak, N. & Xing, Y. PP2A as a master regulator of the cell cycle. Crit. Rev. Biochem. Mol. Biol. 51, 162–184 (2016).
Chen, W. H., Morriss-Kay, G. M. & Copp, A. J. Genesis and prevention of spinal neural tube defects in the curly tail mutant mouse: involvement of retinoic acid and its nuclear receptors RAR-β and RAR-γ. Development 121, 681–691 (1995).
Lara-Ramirez, R., Zieger, E. & Schubert, M. Retinoic acid signaling in spinal cord development. Int. J. Biochem. Cell Biol. 45, 1302–1313 (2013).
Ying, M. et al. The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid-induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARα. Oncogene 35, 4358–4367 (2016).
Sugrue, K. F., Sarkar, A. A., Leatherbury, L. & Zohn, I. E. The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch. Dis. Model. Mech. https://doi.org/10.1242/dmm.036491 (2019).
Cheng, X. et al. F-box protein FBXO30 mediates retinoic acid receptor γ ubiquitination and regulates BMP signaling in neural tube defects. Cell Death Dis. 10, 551 (2019).
Li, H., Zhang, J. & Niswander, L. Zinc deficiency causes neural tube defects through attenuation of p53 ubiquitylation. Development https://doi.org/10.1242/dev.169797 (2018).
Zohn, I. E., Anderson, K. V. & Niswander, L. The Hectd1 ubiquitin ligase is required for development of the head mesenchyme and neural tube closure. Dev. Biol. 306, 208–221 (2007).
Miyajima, N., Maruyama, S., Nonomura, K. & Hatakeyama, S. TRIM36 interacts with the kinetochore protein CENP-H and delays cell cycle progression. Biochem. Biophys. Res. Commun. 381, 383–387 (2009).
Singh, N. et al. A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. Hum. Mol. Genet. 26, 1104–1114 (2017).
Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019).
Baldarelli, R. M. et al. The mouse gene expression database (GXD): 2021 update. Nucleic Acids Res. 49, D924–D931 (2021).
Okamoto, T., Imaizumi, K. & Kaneko, M. The role of tissue-specific ubiquitin ligases, RNF183, RNF186, RNF182 and RNF152, in disease and biological function. Int. J. Mol. Sci. 21, 3921 (2020).
Bosshard, M. et al. Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability. Sci. Rep. 7, 15050 (2017).
Muthusamy, B. et al. Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say–Meyer syndrome. Eur. J. Med. Genet. 63, 103635 (2020).
Herriges, J. C. et al. FGF-regulated ETV transcription factors control FGF–SHH feedback loop in lung branching. Dev. Cell 35, 322–332 (2015).
Zhang, Y. et al. E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors. Proc. Natl Acad. Sci. USA 113, 7557–7562 (2016).
Friez, M. J. et al. HUWE1 mutations in Juberg–Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study. BMJ Open 6, e009537 (2016).
Moortgat, S. et al. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients. Eur. J. Hum. Genet. 26, 64–74 (2018).
Taylor, J. C. et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat. Genet. 47, 717–726 (2015).
Walma, D. A. C. & Yamada, K. M. The extracellular matrix in development. Development 147, 175596 (2020).
Rodriguez-Perez, F. et al. Ubiquitin-dependent remodeling of the actin cytoskeleton drives cell fusion. Dev. Cell 56, 588–601.e9 (2021).
Peuhu, E. et al. SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. EMBO J. 36, 165–182 (2017).
Gladwyn-Ng, I. et al. Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons. Neural. Dev. 11, 7 (2016).
Gladwyn-Ng, I. E. et al. Bacurd2 is a novel interacting partner to Rnd2 which controls radial migration within the developing mammalian cerebral cortex. Neural. Dev. 10, 9 (2015).
Lin, G. N. et al. Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13–Cul3–RhoA pathway in psychiatric diseases. Neuron 85, 742–754 (2015).
Chandhoke, A. S. et al. The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner. Cell Death Differ. 23, 876–888 (2016).
Amar, M. et al. Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling. Mol. Psychiatry 26, 3586–3613 (2021).
Jirka, C., Pak, J. H., Grosgogeat, C. A., Marchetii, M. M. & Gupta, V. A. Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy. Hum. Mol. Genet. 28, 2549–2560 (2019).
Wiszniak, S., Harvey, N. & Schwarz, Q. Cell autonomous roles of Nedd4 in craniofacial bone formation. Dev. Biol. 410, 98–107 (2016).
Zhao, X. et al. Zebrafish cul4a, but not cul4b, modulates cardiac and forelimb development by upregulating tbx5a expression. Hum. Mol. Genet. 24, 853–864 (2015).
Rodriguez, C. et al. A novel human Cdh1 mutation impairs anaphase promoting complex/cyclosome activity resulting in microcephaly, psychomotor retardation, and epilepsy. J. Neurochem 151, 103–115 (2019).
Sui, P. et al. E3 ubiquitin ligase MDM2 acts through p53 to control respiratory progenitor cell number and lung size. Development 146, 179820 (2019).
Garibaldi, M. et al. Core-rod myopathy due to a novel mutation in BTB/POZ domain of KBTBD13 manifesting as late onset LGMD. Acta Neuropathol. Commun. 6, 94 (2018).
Gupta, V. A. et al. Identification of KLHL41 mutations implicates BTB-kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy. Am. J. Hum. Genet. 93, 1108–1117 (2013).
Ravenscroft, G. et al. Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. Am. J. Hum. Genet. 93, 6–18 (2013).
Sambuughin, N. et al. Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am. J. Hum. Genet. 87, 842–847 (2010).
Gupta, V. A. & Beggs, A. H. Kelch proteins: emerging roles in skeletal muscle development and diseases. Skelet. Muscle 4, 11 (2014).
Garg, A. et al. KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. J. Clin. Invest. 124, 3529–3539 (2014).
Ramirez-Martinez, A. et al. KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination. eLife 6, e26439 (2017).
Blondelle, J. et al. Cullin-3 dependent deregulation of ACTN1 represents a new pathogenic mechanism in nemaline myopathy. JCI Insight 4, e125665 (2019).
Delgado-Esteban, M., Garcia-Higuera, I., Maestre, C., Moreno, S. & Almeida, A. APC/C-Cdh1 coordinates neurogenesis and cortical size during development. Nat. Commun. 4, 2879 (2013).
Laos, M., Sulg, M., Herranen, A., Anttonen, T. & Pirvola, U. Indispensable role of Mdm2/p53 interaction during the embryonic and postnatal inner ear development. Sci. Rep. 7, 42216 (2017).
Zhang, Y., Zeng, S. X., Hao, Q. & Lu, H. Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner. Dev. Biol. 423, 34–45 (2017).
Hilliard, S. A., Yao, X. & El-Dahr, S. S. Mdm2 is required for maintenance of the nephrogenic niche. Dev. Biol. 387, 1–14 (2014).
Lessel, D. et al. Dysfunction of the MDM2/p53 axis is linked to premature aging. J. Clin. Invest. 127, 3598–3608 (2017).
Levine, A. J. & Oren, M. The first 30 years of p53: growing ever more complex. Nat. Rev. Cancer 9, 749–758 (2009).
Albrechtsen, N. et al. Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 18, 7706–7717 (1999).
Duan, G. & Walther, D. The roles of post-translational modifications in the context of protein interaction networks. PLoS Comput. Biol. 11, e1004049 (2015).
Dang, F., Nie, L. & Wei, W. Ubiquitin signaling in cell cycle control and tumorigenesis. Cell Death Differ. 28, 427–438 (2021).
Kim, H. S. et al. Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53–Fbxw7/Cdc4 pathway, which controls c-Myc. Cancer Res. 72, 6065–6075 (2012).
Li, M. R. et al. FBXW7 expression is associated with prognosis and chemotherapeutic outcome in Chinese patients with gastric adenocarcinoma. BMC Gastroenterol. 17, 60 (2017).
Lin, J. et al. FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells. Cancer Sci. 109, 1001–1011 (2018).
Meyer, A. E., Furumo, Q., Stelloh, C., Minella, A. C. & Rao, S. Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation. Neoplasia 22, 644–658 (2020).
Valliyammai, N., Nancy, N. K., Sagar, T. G. & Rajkumar, T. Study of NOTCH1 and FBXW7 mutations and its prognostic significance in South Indian T-cell acute lymphoblastic leukemia. J. Pediatr. Hematol. Oncol. 40, e1–e8 (2018).
Adhikary, S. et al. The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell 123, 409–421 (2005).
Myant, K. B. et al. HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. EMBO Mol. Med. 9, 181–197 (2017).
Drainas, A. P. et al. Genome-wide screens implicate loss of cullin ring ligase 3 in persistent proliferation and genome instability in TP53-deficient cells. Cell Rep. 31, 107465 (2020).
Ohta, T. et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 68, 1303–1309 (2008).
Taguchi, K., Motohashi, H. & Yamamoto, M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16, 123–140 (2011).
Ma, B. et al. The SIAH2–NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression. Nat. Commun. 10, 1034 (2019).
Li, Y. et al. WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5–MDM2–p53 pathway. Oncogene 39, 2741–2755 (2020).
Liu, S., Tackmann, N. R., Yang, J. & Zhang, Y. Disruption of the RP–MDM2–p53 pathway accelerates APC loss-induced colorectal tumorigenesis. Oncogene 36, 1374–1383 (2017).
Chang, C. J. et al. p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 13, 317–323 (2011).
Parfenyev, S. et al. Interplay between p53 and non-coding RNAs in the regulation of EMT in breast cancer. Cell Death Dis. 12, 17 (2021).
Sun, L. et al. KLF5 regulates epithelial–mesenchymal transition of liver cancer cells in the context of p53 loss through miR-192 targeting of ZEB2. Cell Adh. Migr. 14, 182–194 (2020).
Ribatti, D., Tamma, R. & Annese, T. Epithelial–mesenchymal transition in cancer: a historical overview. Transl. Oncol. 13, 100773 (2020).
Barrallo-Gimeno, A. & Nieto, M. A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151–3161 (2005).
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Akhtar, N. Hijacking a morphogenesis proteinase for cancer cell invasion. Dev. Cell 47, 135–137 (2018).
Shao, G. et al. The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells. Mol. Cancer 17, 24 (2018).
Na, T. Y., Schecterson, L., Mendonsa, A. M. & Gumbiner, B. M. The functional activity of E-cadherin controls tumor cell metastasis at multiple steps. Proc. Natl Acad. Sci. USA 117, 5931–5937 (2020).
Wiszniak, S. et al. The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties. Dev. Biol. 383, 186–200 (2013).
Wiszniak, S. & Schwarz, Q. Notch signalling defines dorsal root ganglia neuroglial fate choice during early neural crest cell migration. BMC Neurosci. 20, 21 (2019).
Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018).
Tian, P., Liu, D., Sun, L. & Sun, H. Cullin7 promotes epithelialmesenchymal transition of esophageal carcinoma via the ERKSNAI2 signaling pathway. Mol. Med. Rep. 17, 5362–5367 (2018).
Qiu, N. et al. Cullin 7 is a predictor of poor prognosis in breast cancer patients and is involved in the proliferation and invasion of breast cancer cells by regulating the cell cycle and microtubule stability. Oncol. Rep. 39, 603–610 (2018).
Xu, J. et al. Cullin-7 (CUL7) is overexpressed in glioma cells and promotes tumorigenesis via NF-κB activation. J. Exp. Clin. Cancer Res. 39, 59 (2020).
Zhang, D., Yang, G., Li, X., Xu, C. & Ge, H. Inhibition of liver carcinoma cell invasion and metastasis by knockdown of cullin7 in vitro and in vivo. Oncol. Res. 23, 171–181 (2016).
Shi, L., Du, D., Peng, Y., Liu, J. & Long, J. The functional analysis of Cullin 7 E3 ubiquitin ligases in cancer. Oncogenesis 9, 98 (2020).
Sasaki, K. et al. Maternal uniparental isodisomy and heterodisomy on chromosome 6 encompassing a CUL7 gene mutation causing 3M syndrome. Clin. Genet 80, 478–483 (2011).
Simsek-Kiper, P. O. et al. Further expanding the mutational spectrum and investigation of genotype–phenotype correlation in 3M syndrome. Am. J. Med. Genet A 179, 1157–1172 (2019).
Ghandi, M. et al. Next-generation characterization of the cancer cell line encyclopedia. Nature 569, 503–508 (2019).
Huber, C. et al. A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur. J. Hum. Genet 17, 395–400 (2009).
Huber, C. et al. Identification of mutations in CUL7 in 3-M syndrome. Nat. Genet 37, 1119–1124 (2005).
Urquhart, L. Market watch: top drugs and companies by sales in 2017. Nat. Rev. Drug Discov. 17, 232 (2018).
Mullard, A. First targeted protein degrader hits the clinic. Nat. Rev. Drug Discov. https://doi.org/10.1038/d41573-019-00043-6 (2019).
Richardson, P. G. et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116, 679–686 (2010).
Cathcart, A. M. et al. Targeting a helix-in-groove interaction between E1 and E2 blocks ubiquitin transfer. Nat. Chem. Biol. 16, 1218–1226 (2020).
Furihata, H. et al. Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide. Nat. Commun. 11, 4578 (2020).
Naito, M., Ohoka, N. & Shibata, N. SNIPERs — hijacking IAP activity to induce protein degradation. Drug Discov. Today Technol. 31, 35–42 (2019).
Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase–substrate interaction. Nat. Commun. 10, 1402 (2019).
Smith, B. E. et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 10, 131 (2019).
Gabrielsen, M. et al. Identification and characterization of mutations in ubiquitin required for non-covalent dimer formation. Structure 27, 1452–1459.e4 (2019).
Sackton, K. L. et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 514, 646–649 (2014).
Kathman, S. G. et al. A small molecule that switches a ubiquitin ligase from a processive to a distributive enzymatic mechanism. J. Am. Chem. Soc. 137, 12442–12445 (2015).
Watson, E. R. et al. Protein engineering of a ubiquitin-variant inhibitor of APC/C identifies a cryptic K48 ubiquitin chain binding site. Proc. Natl Acad. Sci. USA 116, 17280–17289 (2019).
Brown, N. G. et al. Dual RING E3 architectures regulate multiubiquitination and ubiquitin chain elongation by APC/C. Cell 165, 1440–1453 (2016).
Dueber, E. C. et al. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science 334, 376–380 (2011).
Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, aat0572 (2018).
Schneider, M. et al. The PROTACtable genome. Nat. Rev. Drug Discov. 20, 789–797 (2021).
Ege, N., Bouguenina, H., Tatari, M. & Chopra, R. Phenotypic screening with target identification and validation in the discovery and development of E3 ligase modulators. Cell Chem. Biol. 28, 283–299 (2021).
Hundley, F. V. et al. A comprehensive phenotypic CRISPR–Cas9 screen of the ubiquitin pathway uncovers roles of ubiquitin ligases in mitosis. Mol. Cell 81, 1319–1336.e9 (2021).
Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020).
Hajek, R., Bryce, R., Ro, S., Klencke, B. & Ludwig, H. Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer 12, 415 (2012).
Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN). Br. J. Haematol. 164, 811–821 (2014).
Yamamoto, J. et al. ARID2 is a pomalidomide-dependent CRL4(CRBN) substrate in multiple myeloma cells. Nat. Chem. Biol. 16, 1208–1217 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02959658 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01930708 (2013).
Venci, J. V. & Gandhi, M. A. Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. Ann. Pharmacother. 47, 1697–1702 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04072952 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03888612 (2019).
Assi, R. et al. Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer 124, 2758–2765 (2018).
Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, aal3755 (2017).
Nangaku, M. et al. Randomized clinical trial on the effect of bardoxolone methyl on GFR in diabetic kidney disease patients (TSUBAKI study). Kidney Int. Rep. 5, 879–890 (2020).
Lynch, D. R. et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann. Neurol. 89, 212–225 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04702997 (2021).
Rasco, D. W. et al. A first-in-human study of novel cereblon modulator avadomide (CC-122) in advanced malignancies. Clin. Cancer Res. 25, 90–98 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03834623 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04564703 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04776395 (2021).
Aguilar, A. et al. Discovery of 4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid (AA-115/APG-115): a potent and orally active murine double minute 2 (MDM2) inhibitor in clinical development. J. Med. Chem. 60, 2819–2839 (2017).
Aubry, A., Yu, T. & Bremner, R. Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy. Cell Death Discov. 6, 2 (2020).
Barghout, S. H. et al. Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia. Leukemia 33, 37–51 (2019).
Holzer, P. et al. Discovery of a dihydroisoquinolinone derivative (NVP-CGM097): a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors. J. Med. Chem. 58, 6348–6358 (2015).
Lee, J. K. et al. USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance. Neuro. Oncol. 18, 37–47 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03816319 (2021).
Chan, C. H. et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell 154, 556–568 (2013).
Huang, H. et al. Oridonin triggers Chaperon-mediated proteasomal degradation of BCR-ABL in leukemia. Sci. Rep. 7, 41525 (2017).
Shoji, S. et al. The zinc-binding region (ZBR) fragment of Emi2 can inhibit APC/C by targeting its association with the coactivator Cdc20 and UBE2C-mediated ubiquitylation. FEBS Open Bio. 4, 689–703 (2014).
Vadhan, A. et al. EMI2 expression as a poor prognostic factor in patients with breast cancer. Kaohsiung J. Med. Sci. 36, 640–648 (2020).
Tamanini, E. et al. Discovery of a potent nonpeptidomimetic, small-molecule antagonist of cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). J. Med. Chem. 60, 4611–4625 (2017).
Zeng, S. et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: recent progress and future challenges. Eur. J. Med. Chem. 210, 112981 (2021).
Yuniati, L. et al. Ubiquitylation of the ER-shaping protein lunapark via the CRL3(KLHL12) ubiquitin ligase complex. Cell Rep. 31, 107664 (2020).
Funato, Y. et al. Nucleoredoxin sustains Wnt/β-catenin signaling by retaining a pool of inactive dishevelled protein. CB 20, 1945–1952 (2010).
Rosner, M., Reithofer, M., Fink, D. & Hengstschläger, M. Human embryo models and drug discovery. Int. J. Mol. Sci. 22, 637 (2021).
Chagraoui, J. et al. UM171 preserves epigenetic marks that are reduced in ex vivo culture of human HSCs via potentiation of the CLR3–KBTBD4 complex. Cell Stem Cell 28, 48–62.e46 (2021).
Cohen, S. et al. Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1-2 safety and feasibility study. Lancet Haematol. 7, e134–e145 (2020).
Hershko, A., Eytan, E., Ciechanover, A. & Haas, A. L. Immunochemical analysis of the turnover of ubiquitin-protein conjugates in intact cells. Relationship to the breakdown of abnormal proteins. J. Biol. Chem. 257, 13964–13970 (1982).
Hershko, A., Heller, H., Elias, S. & Ciechanover, A. Components of ubiquitin–protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 258, 8206–8214 (1983).
Waxman, L., Fagan, J. M. & Goldberg, A. L. Demonstration of two distinct high molecular weight proteases in rabbit reticulocytes, one of which degrades ubiquitin conjugates. J. Biol. Chem. 262, 2451–2457 (1987).
Scudellari, M. Protein-slaying drugs could be the next blockbuster therapies. Nature 567, 298–300 (2019).
Acknowledgements
Research conducted by K.M.Y. and D.A.C.W. is supported by the Intramural Research Program of the National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research (ZIA-DE000525 and ZIA-DE000719). Z.C. and A.N.B. receive funding from Cancer Research UK (grant reference DRCNPG\100002) as well as the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan and Diamond Light Source Limited.
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D.A.C.W., K.M.Y., A.N.B. and Z.C. contributed to the conceptualization, writing and revisions of the manuscript. D.A.C.W. and K.M.Y. wrote the first draft and final revisions of the manuscript. Z.C. and A.N.B. reviewed and added to the first draft and revisions of the manuscript. D.A.C.W. and Z.C. prepared the figures.
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Nature Reviews Molecular Cell Biology thanks Izabela Sumara; Yogesh Kulathu, who co-reviewed with Matthew McFarland; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Pre-eclampsia
-
A toxic medical condition during late pregnancy characterized by high blood pressure, oedema and protein in the urine.
- Intrauterine growth restriction
-
Abnormally slow growth of the fetus defined as less than 10% of predicted body weight for gestational age.
- Focal adhesion
-
A subcellular structure containing protein complexes mediating the adhesion of cells to the extracellular matrix.
- Midline
-
A topographical line formed during gastrulation defined by the formation of the notochord that extends from the anterior to the posterior of the embryo that helps define the future embryonic axes.
- Epithelial–mesenchymal transition
-
(EMT). The conversion of epithelial cells to migratory fibroblast-like mesenchymal cells by an intracellular regulatory process.
- Thalidomide
-
A small-molecule drug originally intended for use as a sedative and to relieve pregnancy-induced nausea but found to cause birth defects, particularly limb malformations.
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Cruz Walma, D.A., Chen, Z., Bullock, A.N. et al. Ubiquitin ligases: guardians of mammalian development. Nat Rev Mol Cell Biol 23, 350–367 (2022). https://doi.org/10.1038/s41580-021-00448-5
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DOI: https://doi.org/10.1038/s41580-021-00448-5
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