cancers Review TIF1 Proteins in Genome Stability and Cancer Roisin M. McAvera and Lisa J. Crawford * Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-(0)28-9097-2794 Received: 8 July 2020; Accepted: 27 July 2020; Published: 28 July 2020 Abstract: Genomic instability is a hallmark of cancer cells which results in excessive DNA damage. To counteract this, cells have evolved a tightly regulated DNA damage response (DDR) to rapidly sense DNA damage and promote its repair whilst halting cell cycle progression. The DDR functions predominantly within the context of chromatin and requires the action of chromatin-binding proteins to coordinate the appropriate response. TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases. All four TIF1 proteins are aberrantly expressed across numerous cancer types, and increasing evidence suggests that TIF1 family members can function to maintain genome stability by mediating chromatin-based responses to DNA damage. This review provides an overview of the TIF1 family in cancer, focusing on their roles in DNA repair, chromatin regulation and cell cycle regulation. Keywords: TRIM24; TRIM28; TRIM33; TRIM66; genome stability; DNA damage; cancer 1. Introduction Cells experience tens of thousands of insults to their DNA daily, through both endogenous and exogenous sources. If DNA damage is not properly dealt with, genome instability will arise, making cells susceptible to malignant transformation [1]. As a result, cells have evolved a tightly regulated DNA damage response (DDR)—a complex signalling cascade which aims to rapidly repair DNA whilst halting cell cycle progression. Alternatively, if the damage is deemed irreparable, the DDR will promote apoptosis [1]. Detection and repair of DNA damage occurs within the context of chromatin, the structure and function of which is regulated by post-translational modifications of histones. Research efforts over the past few decades have aimed to gain a better understanding of the proteins involved in its regulation. TRIM24 (TIF1α), TRIM28 (TIF1β/KAP1), TRIM33 (TIF1γ) and TRIM66 (TIF1δ) comprise the transcriptional intermediary family 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large, highly conserved tripartite-motif (TRIM) family of E3 ligases. All four TIF1 proteins have been shown to be aberrantly expressed or mutated in multiple cancer types; however, their role in cancer is still not fully understood. TIF1 proteins have many diverse functions, including a role in transcription, immunity, cell differentiation, DNA repair and mitosis, all of which can be altered in tumorigenesis [2–7]. Increasing evidence has indicated that TIF1 proteins contribute to the maintenance of genome stability. Here, we review their role in genome stability focusing on their alterations in cancer, role in DNA damage repair, cell cycle regulation and their interaction with histones. 2. TIF1 Protein Family Overview TRIM proteins are a large family of over 80 proteins that are generally characterised by a conserved N-terminal RBBC motif made up of a RING domain, either one or two B-boxes (B1 and B2), a coiled-coil Cancers 2020, 12, 2094; doi:10.3390/cancers12082094 www.mdpi.com/journal/cancers Cancers 2020, 12, 2094 2 of 18 Cancers 2020, 12, x 2 of 18 B2),(CC) a domain;coiled-coil and (CC) a highly domain; variable and C-terminal a highly variable [8]. The C-terminal RING domain [8]. confersThe RING E3 ligase domain activity, confers which E3 ligasecan ubiquitinate activity, which substrates can ubiquitinate as part of the substrates ubiquitin as proteasome part of the systemubiquitin (UPS) proteasome [9], whereas system the (UPS) B-box [9],and whereas CC domains the B-box mediate and protein–protein CC domains mediate interactions. protein–protein TRIM proteins interactio are furtherns. TRIM classified proteins by their are furthervariable classified C-terminal by domaintheir variable into eleven C-terminal subfamilies domain (C-I–C-XI) into eleven [10 subfamilies]. (C-I–C-XI) [10]. TRIM24,TRIM24, TRIM28 TRIM28 and and TRIM33 TRIM33 are are classified classified as as th thee C-VI C-VI subfamily subfamily based based on on the the presence presence of of a a plant-homeodomainplant-homeodomain (PHD)(PHD) andand bromodomain bromodomain at at the the C-terminus. C-terminus. Together Together with with TRIM66, TRIM66, which which lacks lacksa RING a RING domain domain but similarly but similarly contains contains two B-boxes, two B-boxes, a CC domain a CC domain and a PHD-bromodomain, and a PHD-bromodomain, TRIM24, TRIM24,TRIM28 TRIM28 and TRIM33 and TRIM33 can be alternativelycan be alternatively classified classified as the TIF1as the family TIF1 fami of proteins.ly of proteins. Through Through their theirPHD-bromodomain, PHD-bromodomain, TIF1 TIF1 proteins prot caneins directlycan directly interact interact with with modified modified histones; histones; PHD PHD fingers fingers read readthe N-terminal the N-terminal domain domain of histone of histone H3, normallyH3, norma thelly methylation the methylation status, status whereas, whereas bromodomains bromodomains read readacetylated acetylated lysines lysines [11,12 ].[11,12]. In addition In addition to their to common their common PHD-bromodomain, PHD-bromodomain, all four all TIF1 four proteins TIF1 proteinscontain acontain TIF-specific a TIF-specific sequence sequence (TSS) which (TSS) is thoughtwhich is to thought be essential to be for essential transcriptional for transcriptional repression. repression.Additionally, Additionally, TRIM24, TRIM28 TRIM24, and TRIM66TRIM28 haveand HP1TRIM66 (heterochromatin have HP1 (heteroc proteinhromatin 1) binding protein domains 1) binding(HPBD) domains which allow (HPBD) the interactionwhich allow of the HP1 interaction family proteins of HP1 through family proteins a PxVxL through motif. The a PxVxL structure motif. of Theindividual structure TIF1 of proteinsindividual is depictedTIF1 proteins in Figure is depicted1. in Figure 1. FigureFigure 1. 1. SchematicSchematic of of the the structure structure of of TIF1 TIF1 family family proteins. proteins. RING—really RING—really interesting interesting new new gene, gene, has has intrinsicintrinsic E3 E3 ligase ligase activity; activity; B1 B1 and and B2—B-box B2—B-box do domains;mains; CC—coiled-coil CC—coiled-coil domain; domain; TSS—TIF1 TSS—TIF1 signature signature sequence;sequence; HPBD—heterochromatinHPBD—heterochromatin protein protein family family binding binding domain; domain; PHD—plant PHD—plant homeodomain homeodomain finger; finger;BROMO—bromodomain. BROMO—bromodomain. TRIM24, TRIM24, TRIM28 TRIM28 and TRIM33 and TRIM33 are classed are classed as the as C-VI the subfamilyC-VI subfamily of TRIM of TRIMproteins proteins based based on their on RBBC their R domainBBC domain and PHD-bromodomain. and PHD-bromodomain. 3.3. TIF1 TIF1 Family Family Alterations Alterations in in Cancer Cancer MembersMembers of of the the TIF1 TIF1 family family are are often often dysregul dysregulatedated in in human human cancers, cancers, most most commonly commonly through through alteredaltered gene gene expression, expression, but but also also through through deletions, deletions, translocations translocations or loss-of-function or loss-of-function mutations. mutations. TIF1 proteinsTIF1 proteins exhibit exhibit both oncogenic both oncogenic and tumour-suppre and tumour-suppressivessive roles depending roles depending on the context, on thesuggesting context, thatsuggesting their functions that their are functions cell-type are specific. cell-type Given specific. their Given altered their expression altered expression in cancer, inthe cancer, TIF1 proteins the TIF1 haveproteins been have proposed been proposed as predictors as predictors of prognosis of prognosis and/or therapeutic and/or therapeutic targets, dependent targets, dependent on cell type on and cell function.type and The function. alterations The alterations of each TIF1 of protein each TIF1 in cancer protein is in outlined cancer isbelow outlined and belowsummarised and summarised in Table 1. in Table1. Cancers 2020, 12, 2094 3 of 18 Table 1. Alterations in the TIF1 family members in cancer, and the proposed function of that gene on cancer progression. 1 WT—Wilms’ tumour; 2 B-ALL—B-cell acute lymphoblastic leukaemia; 3 CMML—chronic myelomonocytic leukaemia; 4 MM—multiple myeloma; 5 Fibroblast growth factor receptor 1. Observed TIF1 Member Cancer Type Alteration Reference Function Cervical High expression Oncogene [13] Glioma High expression Oncogene [14] Head & Neck High expression Oncogene [15] Liver Gene deletion Tumour suppressor [16] TRIM24 Liver N/A Tumour suppressor [17] Lung High expression Oncogene [18] Chromosome Myeloproliferative translocation: Oncogene [19] syndrome FGFR1 5 Nasopharyngeal High expression Oncogene [20] Prostate High expression Oncogene [21] Breast High expression Oncogene [22,23] Gastric High expression Oncogene [24] Glioma High expression Oncogene [25] Liver High expression Oncogene [26] TRIM28 Liver N/A Tumour suppressor [17] Lung (early stage) High expression Tumour suppressor [27] Ovarian High expression Oncogene [28] Pancreatic High expression Oncogene [29] Loss-of-function Renal (WT 1) Tumour suppressor [30] mutation Breast High expression Oncogene [31] Reduced Breast Tumour