DOCSLIB.ORG

Shared and Unique Properties of Ubiquitin and SUMO Interaction Networks in DNA Repair

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Shared and Unique Properties of Ubiquitin and SUMO Interaction Networks in DNA Repair Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Shared and unique properties of ubiquitin and SUMO interaction networks in DNA repair Sjoerd J.L. van Wijk,1 Stefan Mu¨ ller,1 and Ivan Dikic1,2,3 1Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt am Main, Germany; 2Frankfurt Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany In this issue of Genes & Development, Yang and col- residues of target proteins and can be conjugated either as leagues (pp. 1847–1858) identify new components of a monomers or as polymeric chains that are generally small ubiquitin-like modifier (SUMO)-like interaction net- linked through internal lysine residues (Ikeda and Dikic work that orchestrates and fine-tunes the Fanconi anemia 2008). Conjugation of Ub and SUMO typically relies on (FA) pathway and replication-coupled repair. This new the coordinated activity of the catalytic E1–E2–E3 triad, pathway emphasizes the intricate interplay of ubiquitin but compared with Ub, the SUMO conjugation machinery (Ub) and SUMO networks in the DNA damage response. is less complex. SUMO becomes activated by the dimeric UBA2 (Ub-associated domain 2)/AOS1 complex and is subsequently transferred to Ubc9, the only known SUMO E2 (Kerscher et al. 2006; Gareau and Lima 2010). Although Ubiquitin (Ub) and the related small ubiquitin-like mod- Ubc9 is able to transfer SUMO directly to substrates, it ifier (SUMO) (hereafter commonly referred to as ubiqui- typically interacts with SUMO E3 ligases that mediate an tin-like proteins ½UBLs) are part of sophisticated and optimal positioning of the SUMO-loaded E2 and the sub- complex post-translational modification systems (Deribe strate to allow for efficient substrate SUMOylation (Gareau et al. 2010). Ub and SUMO share substantial levels of se- and Lima 2010). Well-characterized E3 SUMO ligases quence homology and become attached to proteins by are Ran-binding protein 2 (RanBP2) and the family of SP- similar conjugation machineries (Kerscher et al. 2006; RING-containing proteins, including the yeast Siz proteins Schulman and Harper 2009; Ye and Rape 2009; Gareau and and the human family of protein inhibitor of STAT (PIAS) Lima 2010). Both modifications are recognized, or read, by proteins. In contrast to SUMOylation, the activation and specialized domains that integrate conjugated UBLs into conjugation of Ub involves at least two E1 enzymes, dynamic and complex interaction networks underlying dozens of E2 enzymes, and hundreds of different Ub E3 many biological processes, like DNA repair pathways (Fig. ligases that specifically interact to select and modify nu- 1A,B; Bergink and Jentsch 2009; Dikic et al. 2009). Ub and merous substrates (Schulman and Harper 2009; Ye and SUMO are actively deconjugated from their substrates in Rape 2009). Finally, both Ub and SUMO are actively hy- a highly controlled spatiotemporal manner, thus assuring drolyzed and removed from their substrates by specialized the plasticity of UBL-mediated protein–protein interac- cysteine proteases: the deubiquitinating enzymes (DUBs) tions (Reyes-Turcu et al. 2009; Grabbe et al. 2011). Impor- and the SUMO-specific proteases (SENP1–3), respectively tantly, some proteins bear integral UBL domains as part of (Reyes-Turcu et al. 2009; Gareau and Lima 2010). larger structures, but do not form conjugates with cellular Only one Ub isoform has been found, and modification proteins (Grabbe and Dikic 2009). Together, the dynamic of substrates with a single ubiquitin (monoubiquitina- nature of Ub- and SUMO-based complex networks form tion) has been associated with alterations in protein the basis for UBL-mediated cellular signaling events. activity and localization (for example, through endocyto- sis, meiosis, and transcriptional regulation) (Ikeda and Ub and SUMO encode multivalent signaling molecules Dikic 2008). PolyUb (polyubiquitination) chains, linked Ub and SUMO are transcribed as precursor molecules through one or several of Ub’s seven lysines, are associ- that require processing prior to their conjugation. Sub- ated with 26S proteasomal degradation, immune signal- sequently, both modifiers are typically attached to lysine ing, and DNA repair (Ikeda and Dikic 2008; Grabbe and Dikic 2009). Ub can also be linked into chains via C-terminal diglycine–N-terminal Met-1 linkages (linear [Keywords: Fanconi anemia; deubiquitinating enzymes; PCNA; SUMO- or head-to-tail ubiquitination) by the LUBAC E3 ligase like domains] complex, and this fulfills essential roles in nuclear factor- 3Corresponding author. E-mail [email protected]. kB (NF-kB) signaling pathways (Iwai and Tokunaga 2009). Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.17593511. While only a single, highly conserved Ub is found in GENES & DEVELOPMENT 25:1763–1769 Ó 2011 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/11; www.genesdev.org 1763 Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press van Wijk et al. responses by interactions with effector proteins contain- ing specialized UBDs and SUMO-interacting motifs (SIMs), respectively (Hecker et al. 2006; Grabbe et al. 2011). Numerous studies have addressed the structures, functions, and Ub specificities of a wide variety of UBDs, of which >20 distinct families have been identified so far (Dikic et al. 2009). These UBDs employ specialized structural and functional characteristics that determine their ability to recognize and bind to different types of modifications. For example, the Pru (Plexstrin receptor for Ub) of the proteasomal receptor Rpn13 or UBA of several shuttling receptors binds preferentially to Lys 48 Ub chains (Raasi et al. 2005; Husnjak et al. 2008), whereas the NZF (Npl4-like zinc finger) domain of TAK1-binding protein 2 (TAB2) preferentially binds to Lys 63-linked Figure 1. UBD and SIM interaction surfaces on Ub and SUMO polyUb chains with much higher affinity than Lys 48 are not conserved. Structural alignment of a molecular ribbon chains (Kulathu et al. 2009; Sato et al. 2009), and ubiquitin representation of Ub (magenta; Protein Data Bank ½PDB: 1aar) binding by the ABIN and NEMO (UBAN) domain of the and SUMO-3 (cyan; PDB: 2rpq). On Ub, the canonical Leu 8, Ile 44, and Val 70 residues that contact UBDs are indicated (see IKK adaptor NEMO specifically binds to linear ubiquitin Dikic et al. 2009). Val 30, Phe 32, Ile 34, Thr 38, and Leu 43 on chains (Rahighi et al. 2009). Importantly, UBDs not only SUMO3 have been shown to contact a canonical SIM in MCAF1 recognize ubiquitin conjugates but can also function as (the MBD1 ½methyl-CpG-binding domain protein 1-containing readers for proteins, which contain ubiquitin-like domains chromatin-associated factor 1) (Sekiyama et al. 2008). A similar (Grabbe et al. 2011). A paradigm stems from the Rad23 surface in SUMO1 or SUMO2/3 has also been shown to be protein, which has an N-terminal ubiquitin-like domain involved in binding to the hydrophobic SIM region of PIAS family that binds to the UBD of the 26S proteasomal ubiquitin members (Hecker et al. 2006). Remarkably, positively charged receptor RPN10/S5 (Dantuma et al. 2009). Rad23 is in- residues in SUMO paralogs, including Lys 33 of SUMO2, which is volved in nucleotide excision repair (NER) via the XPC conserved in the SLD2 of UAF1, contribute to SIM binding. Note (xeroderma pigmentosum group C) protein complex. XPC that opposite surfaces on SUMO and Ub serve as interaction platforms for the respective binding modules. The image was has been shown to interact with RAD23A and RAD23B, generated using University of California at San Francisco Chimera which contain an N-terminal ubiquitin-like domain and (release date May 24, 2011; http://www.cgl.ucsf.edu/chimera). C-terminal UBA domains (Bergink and Jentsch 2009). Similar to what has been observed for ubiquitin, signaling by SUMO often relies on the recognition of lower and higher eukaryotes, four SUMO forms (SUMO the post-translational mark by a specialized interaction 1–4) have been identified in humans. Among these, only module, termed the SIM (Hecker et al. 2006). In many SUMO1–3 are conjugated to substrates. SUMO2 and cases SIM-mediated interactions direct the assembly of SUMO3 share 97% sequence identity and show ;50% protein complexes, like the SIM-dependent targeting of amino acid identity with SUMO1. SUMO2/3 are able to CENP-E and Daxx to the centromere or PML nuclear form SUMO chains mainly via lysine residue Lys 11, bodies, respectively (Lin et al. 2006; Zhang et al. 2008). while modification by SUMO1 preferentially occurs as SIMs have been identified in a wide range of proteins and a monomodification (Geoffroy and Hay 2009; Gareau and are typically characterized by a short consensus sequence Lima 2010). SUMO1 may also be conjugated to the end of of hydrophobic residues ½(V/I/L)-X-(V/I/L)-(V/I/L) or (V/I/ an extending SUMO2/3 chain, thereby terminating chain L)-(V/I/L)-X-(V/I/L), which folds into a small b sheet that elongation (Gareau and Lima 2010). Like ubiquitination, becomes inserted between an a helix and a b sheet of the modification by SUMO generally acts to modulate the interacting SUMO molecule (Hecker et al. 2006). Se- dynamics of protein–protein interactions, thereby control- quence variations within the hydrophobic core of some ling critical cellular pathways. Distinctive functions of characterized SIMs may allow selective recognition of mono- or polymodification with SUMO are just beginning distinct SUMO paralogs (Gareau and Lima 2010). Nota- to be uncovered (Ulrich 2008). Interestingly, however, bly, in some cases, acidic residues are flanking the hy- polymeric chains of SUMO2/3 can trigger substrate ubiq- drophobic core, and NMR studies suggest that the acidic uitination by recruiting SUMO-targeted ubiquitin ligases stretch mediates electrostatic interactions with a surface (STUbL) such as Slx5/8 proteins in Saccharomyces cer- area formed by basic residues of SUMO (Fig.
Load more

Recommended publications
  • Isoform-Specific Monobody Inhibitors of Small Ubiquitin-Related Modifiers Engineered Using Structure-Guided Library Design
    Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design Ryan N. Gilbretha, Khue Truongb, Ikenna Madub, Akiko Koidea, John B. Wojcika, Nan-Sheng Lia, Joseph A. Piccirillia,c, Yuan Chenb, and Shohei Koidea,1 aDepartment of Biochemistry and Molecular Biology, and cDepartment of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637; and bDepartment of Molecular Medicine, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, CA 91010 Edited by David Baker, University of Washington, Seattle, WA, and approved March 16, 2011 (received for review February 10, 2011) Discriminating closely related molecules remains a major challenge which SUMOylation alters protein function appears to be in the engineering of binding proteins and inhibitors. Here we through SUMO-mediated interactions with other proteins con- report the development of highly selective inhibitors of small ubi- taining a short peptide motif known as a SUMO-interacting motif quitin-related modifier (SUMO) family proteins. SUMOylation is (SIM) (4, 7, 8). involved in the regulation of diverse cellular processes. Functional There are few inhibitors of SUMO/SIM interactions, a defi- differences between two major SUMO isoforms in humans, SUMO1 ciency that limits our ability to finely dissect SUMO biology. In and SUMO2∕3, are thought to arise from distinct interactions the only reported example of such an inhibitor, a SIM-containing mediated by each isoform with other proteins containing SUMO- linear peptide was used to inhibit SUMO/SIM interactions, estab- interacting motifs (SIMs). However, the roles of such isoform- lishing their importance in coordinating DNA repair by nonho- specific interactions are largely uncharacterized due in part to the mologous end joining (9).
    [Show full text]
  • Open Full Page
    CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Prokaryotic Ubiquitin-Like Protein Remains Intrinsically Disordered When Covalently Attached to Proteasomal Target Proteins Jonas Barandun1,2, Fred F
    Barandun et al. BMC Structural Biology (2017) 17:1 DOI 10.1186/s12900-017-0072-1 RESEARCH ARTICLE Open Access Prokaryotic ubiquitin-like protein remains intrinsically disordered when covalently attached to proteasomal target proteins Jonas Barandun1,2, Fred F. Damberger1, Cyrille L. Delley1, Juerg Laederach1, Frédéric H. T. Allain1 and Eilika Weber-Ban1* Abstract Background: The post-translational modification pathway referred to as pupylation marks proteins for proteasomal degradation in Mycobacterium tuberculosis and other actinobacteria by covalently attaching the small protein Pup (prokaryotic ubiquitin-like protein) to target lysine residues. In contrast to the functionally analogous eukaryotic ubiquitin, Pup is intrinsically disordered in its free form. Its unfolded state allows Pup to adopt different structures upon interaction with different binding partners like the Pup ligase PafA and the proteasomal ATPase Mpa. While the disordered behavior of free Pup has been well characterized, it remained unknown whether Pup adopts a distinct structure when attached to a substrate. Results: Using a combination of NMR experiments and biochemical analysis we demonstrate that Pup remains unstructured when ligated to two well-established pupylation substrates targeted for proteasomal degradation in Mycobacterium tuberculosis, malonyl transacylase (FabD) and ketopantoyl hydroxylmethyltransferase (PanB). Isotopically labeled Pup was linked to FabD and PanB by in vitro pupylation to generate homogeneously pupylated substrates suitable for NMR analysis. The single target lysine of PanB was identified by a combination of mass spectroscopy and mutational analysis. Chemical shift comparison between Pup in its free form and ligated to substrate reveals intrinsic disorder of Pup in the conjugate. Conclusion: When linked to the proteasomal substrates FabD and PanB, Pup is unstructured and retains the ability to interact with its different binding partners.
    [Show full text]
  • Yichen – Structure and Allostery of the Chaperonin Groel. Allosteric
    Literature Lunch 5-1-13 Yichen – J Mol Biol. 2013 May 13;425(9):1476-87. doi: 10.1016/j.jmb.2012.11.028. Epub 2012 Nov 24. Structure and Allostery of the Chaperonin GroEL. Saibil HR, Fenton WA, Clare DK, Horwich AL. Source Crystallography and Institute of Structural and Molecular Biology, Birkbeck College London, Malet Street, London WC1E 7HX, UK. Abstract Chaperonins are intricate allosteric machines formed of two back-to-back, stacked rings of subunits presenting end cavities lined with hydrophobic binding sites for nonnative polypeptides. Once bound, substrates are subjected to forceful, concerted movements that result in their ejection from the binding surface and simultaneous encapsulation inside a hydrophilic chamber that favors their folding. Here, we review the allosteric machine movements that are choreographed by ATP binding, which triggers concerted tilting and twisting of subunit domains. These movements distort the ring of hydrophobic binding sites and split it apart, potentially unfolding the multiply bound substrate. Then, GroES binding is accompanied by a 100° twist of the binding domains that removes the hydrophobic sites from the cavity lining and forms the folding chamber. ATP hydrolysis is not needed for a single round of binding and encapsulation but is necessary to allow the next round of ATP binding in the opposite ring. It is this remote ATP binding that triggers dismantling of the folding chamber and release of the encapsulated substrate, whether folded or not. The basis for these ordered actions is an elegant system of nested cooperativity of the ATPase machinery. ATP binds to a ring with positive cooperativity, and movements of the interlinked subunit domains are concerted.
    [Show full text]
  • FANCJ Regulates the Stability of FANCD2/FANCI Proteins and Protects Them from Proteasome and Caspase-3 Dependent Degradation
    FANCJ regulates the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation Komaraiah Palle, Ph.D. (Kumar) Assistant Professor of Oncologic Sciences Abraham Mitchell Cancer Research Scholar Mitchell Cancer Institute University of South Alabama Outline • Fanconi anemia (FA) pathway • Role of FA pathway in Genome maintenance • FANCJ and FANCD2 functional relationship • FANCJ-mediated DDR in response to Fork-stalling Fanconi Anemia • Rare, inherited blood disorder. • 1:130,000 births Guido Fanconi 1892-1979 • Affects men and women equally. • Affects all racial and ethnic groups – higher incidence in Ashkenazi Jews and Afrikaners Birth Defects Fanconi anemia pathway • FA is a rare chromosome instability syndrome • Autosomal recessive disorder (or X-linked) • Developmental abnormalities • 17 complementation groups identified to date • FA pathway is involved in DNA repair • Increased cancer susceptibility - many patients develop AML - in adults solid tumors Fanconi Anemia is an aplastic anemia FA patients are prone to multiple types of solid tumors • Increased incidence and earlier onset cancers: oral cavity, GI and genital and reproductive tract head and neck breast esophagus skin liver brain Why? FA is a DNA repair disorder • FA caused by mutations in 17 genes: FANCA FANCF FANCM FANCB FANCG/XRCC9 FANCN/PALB2 FANCC FANCI RAD51C/FANCO FANCD1/BRCA2 FANCJ SLX4/FANCP FANCD2 FANCL ERCC2/XPF/FANCQ FANCE BRCA1/FANCS • FA genes function in DNA repair processes • FA patient cells are highly sensitive
    [Show full text]
  • DNA Damage Response and Cancer Therapeutics Through the Lens of the Fanconi Anemia DNA Repair Pathway Sonali Bhattacharjee* and Saikat Nandi*
    Bhattacharjee and Nandi Cell Communication and Signaling (2017) 15:41 DOI 10.1186/s12964-017-0195-9 REVIEW Open Access DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway Sonali Bhattacharjee* and Saikat Nandi* Abstract Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions. The multi-protein network is tightly regulated by complex mechanisms, such as ubiquitination, phosphorylation, and degradation signals that are critical for the maintenance of genome integrity and suppressing tumorigenesis. Here, we discuss recent advances in our understanding of how the FA proteins participate in ICL repair and regulation of the FA signaling network that assures the safeguard of the genome. We further discuss the potential application of designing small molecule inhibitors that inhibit the FA pathway and are synthetic lethal with DNA repair enzymes that can be used for cancer therapeutics. Keywords: DNA repair, Fanconi Anemia (FA) signaling network, DNA damage response, Cancer therapeutics, Synthetic lethality, Combination Therapy Genomic instability, Interstrand crosslink (ICL), Homologous recombination, Translesion synthesis Background Additional clinical features included microcephaly, vitiligo Fanconi Anemia (FA), a rare genetic cancer-susceptibility and hypoplasia of the testes [8]. After nearly four decades syndrome is a recessive autosomal or X-linked genetic dis- another article reported an accumulation of large number ease [1–3].
    [Show full text]
  • Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients
    cancers Article Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients Jesús del Valle 1,2,3 , Paula Rofes 1,2,3 , José Marcos Moreno-Cabrera 1,2,3 , Adriana López-Dóriga 4,5, Sami Belhadj 1,2,3 , Gardenia Vargas-Parra 1,2,3, Àlex Teulé 1,2,6, Raquel Cuesta 1,2,3, Xavier Muñoz 1,2,3, Olga Campos 1,2,3,Mónica Salinas 1,2, Rafael de Cid 7, Joan Brunet 1,2,3, Sara González 1,2,3, Gabriel Capellá 1,2,3 , Marta Pineda 1,2,3 , Lídia Feliubadaló 1,2,3 and Conxi Lázaro 1,2,3,* 1 Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL-IGTP-IDIBGI, 08908 Hospitalet de Llobregat, Spain; [email protected] (J.d.V.); [email protected] (P.R.); [email protected] (J.M.M.-C.); [email protected] (S.B.); [email protected] (G.V.-P.); [email protected] (À.T.); [email protected] (R.C.); [email protected] (X.M.); [email protected] (O.C.); [email protected] (M.S.); [email protected] (J.B.); [email protected] (S.G.); [email protected] (G.C.); [email protected] (M.P.); [email protected] (L.F.) 2 Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, 08908 Hospitalet de Llobregat, Spain 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain 4 Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, 08908 Hospitalet de Llobregat, Spain; [email protected] 5 Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain 6 Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, 08908 Hospitalet de Llobregat, Spain 7 Genomes for Life—GCAT lab Group, Institut Germans Trias i Pujol (IGTP), 08916 Badalona, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-93-2607145 Received: 7 February 2020; Accepted: 25 March 2020; Published: 30 March 2020 Abstract: Fanconi anemia (FA) is caused by biallelic mutations in FA genes.
    [Show full text]
  • SUMO and Ubiquitin in the Nucleus: Different Functions, Similar Mechanisms?
    Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Grace Gill1 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA The small ubiquitin-related modifier SUMO posttrans- tin, SUMO modification regulates protein localization lationally modifies many proteins with roles in diverse and activity. processes including regulation of transcription, chroma- This review focuses on recent advances in our under- tin structure, and DNA repair. Similar to nonproteolytic standing of SUMO function and regulation, drawing on a roles of ubiquitin, SUMO modification regulates protein limited set of examples relating to gene expression, chro- localization and activity. Some proteins can be modified matin structure, and DNA repair. Comparison of SUMO by SUMO and ubiquitin, but with distinct functional and ubiquitin activities in the nucleus reveals interest- consequences. It is possible that the effects of ubiquiti- ing differences in function and suggests surprising simi- nation and SUMOylation are both largely due to binding larities in mechanism. Thus, for example, modification of proteins bearing specific interaction domains. Both of transcription factors and histones by ubiquitin is gen- modifications are reversible, and in some cases dynamic erally associated with increased gene expression whereas cycles of modification may be required for activity. Stud- modification of transcription factors and histones by ies of SUMO and ubiquitin in the nucleus are yielding SUMO is generally associated with decreased gene ex- new insights into regulation of gene expression, genome pression. In some cases, SUMO and ubiquitin may di- maintenance, and signal transduction.
    [Show full text]
  • Progress in the Discovery of Small Molecule Modulators of Desumoylation
    Curr. Issues Mol. Biol. (2020) 35: 17-34. Progress in the Discovery of Small Molecule Modulators of DeSUMOylation Shiyao Chen, Duoling Dong, Weixiang Xin and Huchen Zhou* School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. *Correspondence: [email protected] htps://doi.org/10.21775/cimb.035.017 Abstract protein–protein interactions, gene transcription, SUMOylation and DeSUMOylation are reversible genome integrity, and DNA replication and repair protein post-translational modifcation (PTM) (Wilkinson and Henley, 2010; Vierstra, 2012; processes involving small ubiquitin-like modifer Bailey et al., 2016). In 1995, Meluh and Koshland (SUMO) proteins. Tese processes have indis- (1995) identifed Smt3 in Saccharomyces cerevi- pensable roles in various cellular processes, such siae, which is the earliest report within this fled. as subcellular localization, gene transcription, and Two years later, based on the sequence similarity DNA replication and repair. Over the past decade, between ubiquitin and a new 11.5-kDa protein, increasing atention has been given to SUMO- ubiquitin/SMT3, the name SUMO was formally related pathways as potential therapeutic targets. proposed for the frst time (Mahajan et al., 1997). Te Sentrin/SUMO-specifc protease (SENP), Although SUMO modifcation is closely which is responsible for deSUMOylation, has related to the progression of various diseases, such been proposed as a potential therapeutic target as cancers and cardiac disorders, it has aroused in the treatment of cancers and cardiac disorders. increasing atention as a potential therapeutic target Unfortunately, no SENP inhibitor has yet reached in recent years, especially concerning the Sentrin/ clinical trials. In this review, we focus on advances SUMO-specifc protease (SENP), which is the key in the development of SENP inhibitors in the past regulator of deSUMOylation.
    [Show full text]
  • Epigenetic Regulation of DNA Repair Genes and Implications for Tumor Therapy ⁎ ⁎ Markus Christmann , Bernd Kaina
    Mutation Research-Reviews in Mutation Research xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Mutation Research-Reviews in Mutation Research journal homepage: www.elsevier.com/locate/mutrev Review Epigenetic regulation of DNA repair genes and implications for tumor therapy ⁎ ⁎ Markus Christmann , Bernd Kaina Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany ARTICLE INFO ABSTRACT Keywords: DNA repair represents the first barrier against genotoxic stress causing metabolic changes, inflammation and DNA repair cancer. Besides its role in preventing cancer, DNA repair needs also to be considered during cancer treatment Genotoxic stress with radiation and DNA damaging drugs as it impacts therapy outcome. The DNA repair capacity is mainly Epigenetic silencing governed by the expression level of repair genes. Alterations in the expression of repair genes can occur due to tumor formation mutations in their coding or promoter region, changes in the expression of transcription factors activating or Cancer therapy repressing these genes, and/or epigenetic factors changing histone modifications and CpG promoter methylation MGMT Promoter methylation or demethylation levels. In this review we provide an overview on the epigenetic regulation of DNA repair genes. GADD45 We summarize the mechanisms underlying CpG methylation and demethylation, with de novo methyl- TET transferases and DNA repair involved in gain and loss of CpG methylation, respectively. We discuss the role of p53 components of the DNA damage response, p53, PARP-1 and GADD45a on the regulation of the DNA (cytosine-5)- methyltransferase DNMT1, the key enzyme responsible for gene silencing. We stress the relevance of epigenetic silencing of DNA repair genes for tumor formation and tumor therapy.
    [Show full text]
  • Loss of Conserved Ubiquitylation Sites in Conserved Proteins During Human Evolution
    INTERNATIONAL JOURNAL OF MOleCular meDICine 42: 2203-2212, 2018 Loss of conserved ubiquitylation sites in conserved proteins during human evolution DONGBIN PARK, CHUL JUN GOH, HYEIN KIM, JI SEOK LEE and YOONSOO HAHN Department of Life Science, Chung‑Ang University, Seoul 06974, Republic of Korea Received January 30, 2018; Accepted July 6, 2018 DOI: 10.3892/ijmm.2018.3772 Abstract. Ubiquitylation of lysine residues in proteins serves Introduction a pivotal role in the efficient removal of misfolded or unused proteins and in the control of various regulatory pathways Ubiquitylation, in which the highly conserved 76‑residue poly- by monitoring protein activity that may lead to protein peptide ubiquitin is covalently attached to a lysine residue of degradation. The loss of ubiquitylated lysines may affect substrate proteins, mediates the targeted destruction of ubiq- the ubiquitin‑mediated regulatory network and result in the uitylated proteins by the ubiquitin‑proteasome system (1‑4). emergence of novel phenotypes. The present study analyzed The ubiquitin‑mediated protein degradation pathway serves a mouse ubiquitylation data and orthologous proteins from crucial role in the efficient and specific removal of misfolded 62 mammals to identify 193 conserved ubiquitylation sites from proteins and certain key regulatory proteins (5,6). Ubiquitin 169 proteins that were lost in the Euarchonta lineage leading and other ubiquitin‑like proteins, including autophagy‑related to humans. A total of 8 proteins, including betaine homo- protein 8, Ubiquitin‑like
    [Show full text]