Atlas of Genetics and Cytogenetics in Oncology and Haematology

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HLTF (-like transcription factor) Ludovic Dhont, Alexandra Belayew Molecular Biology, Health Institute, University of Mons, Mons, Belgium. [email protected]

Published in Atlas Database: November 2016 Online updated version : http://AtlasGeneticsOncology.org/Genes/HLTFID42332ch3q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68527/11-2016-HLTFID42332ch3q24.pdf DOI: 10.4267/2042/68527 This article is an update of : HLTF (helicase-like transcription factor). Atlas Genet Cytogenet Oncol Haematol Dimitrova J, Belayew A. HLTF (helicase-like transcription factor). Atlas Genet Cytogenet Oncol Haematol 2010;14(10)

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Abstract domains involved in DNA repair. HLTF is a transcription factor - The Helicase-Like These data support a role of tumor suppressor Transcription Factor (HLTF/SMARCA3) belongs to for HLTF. the family of SWI/SNF proteins that use the energy The first association between HLTF inactivation and of ATP hydrolysis to remodel in a variety tumorigenesis was shown when hypermethylation of of cellular processes. the HLTF promoter was detected in 43% of primary Several groups independently isolated HLTF colon tumors and 22-55% of gastric cancers. through its capacity to selectively interact with a Moreover, HLTF deficiency in Apc-/+ mice induced DNA cis-element in the promoter or enhancer of the transition from colon adenocarcinoma to a different involved in cardiac development carcinoma with high chromosomal instability. In during embryogenesis, cell cycle, collagen head and neck, thyroid and uterus (cervix) cancers, biogenesis, cell motility and angiogenesis. an increased expression of two HLTF protein forms HLTF is a key element in DNA Damage Tolerance truncated in the carboxyl-terminal domain following pathways - HLTF plays a role in DNA Damage alternative mRNA splicing was reported. Tolerance, especially in (i) translesion synthesis and These truncated HLTF forms have lost their DNA (ii) template switching pathways (fork regression repair ability and might also have gained functions and strand invasion). favouring cancer. HLTF is an E3 ubiquitin ligase targeting PCNA Keywords (K164) that results in DTT activation. HLTF; Transcription factor; Post-replication DNA The E3 ubiquitin ligase, translocase and HIRAN Repair; DNA damage tolerance pathways; E3- catalytic domain are the HLTF core activities. A key ubiquitin ligase; Cell Cycle; Cancer; Epigenetics; role in DNA repair was confirmed in vivo, in 2 promoter methylation; Alternative splicing. different Hltf null mouse models and showed that Hltf loss compromises error-free DNA replication and modulates mutagenesis by regulating proteins Identity involved in the G2/M phase transition of the cell HGNC (Hugo): HLTF cycle in mouse heart and brain. HLTF is a tumor suppressor gene - In cancer, two Location: 3q24 mechanisms of HLTF inactivation are reported: (i) Other names: HIP116, HIP116A, HLTF1, RNF80, hypermethylation of its promoter and (ii) expression SMARCA3, SNF2L3, ZBU1, RUSH of truncated protein forms that have lost

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Figure 1. Graphic representation of HLTF protein with its domains. Exon/intron structure of the human HLTF gene (upper line, after GenBank no.AJ418064) and domain organisation of the largest encoded protein (lower line after Genbank Z46606) (Debauve et al., 2008). The thin tilted lines link the 3' end of each exon to the last amino acid it encodes, except for exons 1 and 25 where they indicate the 1st and last protein residues, respectively. The different protein domains are boxed: DBD (DNA binding domain), HIRAN (Hip116-Rad5 N-terminal domain; Lyer et al., 2006), SNF2_N (SNF2 family N-terminal domain), I to VI (7 helicase domains), RING (zinc finger domain associated with E3 ubiquitin ligase activity).

Met123 in the same reading frame generates HLTF DNA/RNA proteins of 115kDa and 110kDa, respectively (Ding Description et al., 1996). The rabbit orthologue of human HLTFMet123 is the The HLTF gene is located at 3q 25.1-26.1 (Lin et al., RUSH-1alpha 113kDa protein; RUSH-1beta is a 1995); it is 56.4kb long and contains 26 exons. 95kDa truncated version that results from alternative Transcription splicing of a 57bp exon (Chilton et al., 2008). The alternative splicing of intron 25, mapped in the In Hela cells two protein variants resulting from 3'UTR, produces two mRNA of 5.4 and 4.5kb with alternative splicing of exon 20 or intron 21 were identical coding capacity. Additional alternative observed: HLTF1ΔA (83kDa) and HLTF1ΔB splicing of exon 20 or intron 21 was observed in (95kDa). These proteins have lost domains needed HeLa cells (Capouillez et al., 2009). for DNA repair activity (Capouillez et al., 2009). In the rabbit, the RUSH 1alpha and beta protein Description variants result from progesterone- or estrogen- HLTF belong to the SWI/SNF family of chromatin dependent alternative splicing of the mRNA, remodelling enzymes. respectively (Hayward-Lester et al., 1996). The protein contains: (a) a HIP116 Rad5p N- In the mouse, a transcriptome analysis of the heart terminal (HIRAN) domain embedded in a larger and brain revealed the expression of a full-lenght DNA-binding domain, (b) a Sucrose Non- HLTF RNA isoform (exons 1-25) and a spliced Fermenting 2 (SNF2) amino-terminal dimerization isoform (exons 1-21 + intron 21) in a ratio 26 :1 domain, (c) seven conserved DNA helicase/ATPase (heart) and 5 :1 (brain) (Helmer et al., 2013 and domains, characteristic of SWI/SNF2 family 2013a). members and (d) a Really Interesting New Gene Pseudogene (RING) finger domain (Dhont et al., 2015) (see None. diagram 1). The HLTF1ΔA protein form has lost the RING domain and the last 3 helicase domains. Protein HLTF1ΔB form has only lost the last 3 helicase domains (Capouillez et al., 2009). Note Both proteins are predicted to have lost DNA repair Translation of alternatively spliced mRNAs: activity. The alternative use of start codons Met1 and

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Expression Qing and colleagues showed that HLTF was positively regulated by USP7, a deubiquitination Development: enzyme, which interacts with HLTF in vitro and in During mouse embryogenesis, Zbu1 (mouse HLTF) vivo and stabilizes it without any competition with transcripts are detected relatively late in foetal CHFR (Qing et al., 2011). development and increase in neonatal stages, Cancer: whereas the protein accumulates asynchronously in Two lines of evidence have lead to the conclusion heart, skeletal muscle, and brain. In adult human that HLTF was a tumor suppressor gene. A first set tissues, alternatively spliced Zbu1 transcripts are of publications showed aberrant hypermethylation of ubiquitous with highest expression in the same the HLTF promoter leading to its silencing in various tissues (Gong et al., 1997). Sandhu and colleagues cancer types. Then two publications demonstrated built a Hltf -/- mouse by replacing Hltf with LacZ, in that the HLTF protein was involved in post order to track Hltf expression during embryogenesis. replication DNA repair and that its inactivation leads They found that Hltf was specifically expressed in to rearrangements. the heart at an early developmental stage (E8.5 to The HLTF promotor is hypermethylated in 43% of E9.5). Hltf exhibited a broader expression pattern at primary colon cancer (Moinova et al., 2002) and is E10.5, with LacZ signals detected in somites, frequently methylated in adenomas and branchial arches, limb bud and brain. At later hepatocarcinomas. Kim et al. (2006) found that the embryonic developmental stages, such as E16.5, Hltf HLTF inactivation by promoter hypermethylation showed wide and strong expression in many tissues, was associated with the first stages of including heart, lung, liver, kidney, spleen and carcinogenesis. For a detailed analysis, see Dhont et pancreas. This wide-spread expression of Hltf was al., 2015. also observed in adult mice. In both adult intestine and colon, Hltf expression was mainly detected in Localisation the crypts and in the intestinal epithelial cells Intracellular localisation. (Sandhu et al., 2012). In head and neck, and thyroid cancer progression a Expression profile: significant shift of HLTF expression from the Find link to expression profile: HLTF (T1D cytoplasm toward the nuclear compartment was database) observed (Capouillez et al., 2008). Transcription regulation: In the uterus rabbit HLTF expression is repressed by Function estrogens and induced by progesterone (Hayward- DNA-binding protein: Lester et al., 1996). HLTF was isolated independently (and given The rabbit HLTF (RUSH) promotor has no TATAA different names) by different groups based on its box and the transcription start site maps on an interaction with different genes (see table below). initiator/downstream element (Inr-DPE). Two Sp1/Sp3 binding sites in the proximal promoter Name Target gene Reference repress basal transcription. These features are HIP116 HIV promoter; SV40 conserved in the human gene promoter. In addition Sheridan et al., 1995 the rabbit HLTF promoter is repressed by NF-Y and (human) enhancers HLTF PAI-1 (SERPINE1) HLTF itself and activated by progesterone Ding et al., 1996 (Hewetson and Chilton, 2003). In response to (human) promoter progesterone the HLTF (RUSH 1alpha) protein P113 PAI-1 (SERPINE1) Zhang et al., 1996 binds to a distal site in the promoter of its own gene (mouse) promoter and is involved in DNA looping by interaction with RUSH Hayward-Lester et Uteroglobin promoter Egr-1/c-Rel bound to one of the Sp1/Sp3 sites (rabbit) al., 1996 mentioned above. This interaction represses Zbu1 Myosin light chain Gong et al., 1997 progesterone induction (Chilton and Hewetson, (mouse) enhancer 2008). Protein regulation: HLTF B-globin Mahajan and Kim and colleagues showed that HLTF undergoes a (human) control region Weissman, 2002 negative regulation by CHFR, a E3 ubiquitin ligase. Both proteins interact in vitro and in vivo and as Transcriptional activity: CHFR levels increase, HLTF levels decrease The HLTFMet123 variant activates the SERPINE1 accordingly. Proteasome inhibitor (MG132) reverts (PAI-1) promoter in synergy with Sp1 or Sp3. This this effect on HLTF stability, suggesting its synergy involves protein/protein and protein/DNA degradation is mediated by ubiquitin-proteasome interactions (Ding et al., 1996; Ding et al., 1999). system. They also proved that HLTF half-life was Two different consensus sequences recognized by shortened in presence of CHFR (Kim et al., 2010). HLTF were discovered: (A/G)G(T/C)(G/T)G (Ding

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et al., 1996) and (C/A)C(T/A)TN(T/G) (Hayward- both involved in DNA replication and repair Lester et al., 1996). The latter one was used by (MacKay et al., 2009). Genomatix (MatInspector; Cartharius et al., 2005) to When DNA damaged, the replication fork stalls and develop an algoritm to find putative HLTF binding leads to cell death. DNA damage tolerance pathways sites. are activated through PCNA ubiquitination. RAD6- HLTF can activate gene transcription either alone or and HLTF control this pathways. HLTF is with different protein partners according to the cell preferentially recruited when DNA is damaged by type and the target gene (i.e., SP1/ SP3 for UV and inhibits its counterpart SHPRH in that case. SERPINE1 (Ding et al., 1996 and 1999), NONO and However, if DNA is damaged by methyl-methan SFPQ for PRL (Guillaumond et al., 2011), LEF1 and sulfonate (MMS), HLTF degradation is triggered MITF for OCA2 (Visser et al., 2012)). It binds a and SHPRH is activated (Lin et al., 2011). HLTF promoter (i.e. SERPINE1 or PRL) or an enhancer activates translesion synthesis by monoubiquinating (i.e., intron 86 of HERC2 for OCA2 expression) and PCNA and by recruiting the error-free DNA involves a long distance chromatin looping (Visser polymerase POLH ID: 303> (Polη). HLTF also et al., 2012) for PRL expression (Guillaumond et al., activates template switching by polyubiquitinating 2011) and its own downregulation mediated by Erg- PCNA. Its HIRAN domain is essential in the 1 and REL (Hewetson et al., 2008). See also Dhont recognition of stalled DNA replication fork (a 3'- et al., 2015. hydroxyl group (3'-OH) on the nascent leading Chromatin remodelling: strand, which mimics a site of two unpaired Similarly to other SNF/SWI proteins, HLTF could nucleotides) and its restart (Kile et al., 2015), in play a role in chromatin remodelling. It has the 7 concert with it helicase domains (Blastyàk et al., helicase domains and presents a DNA-dependent 2010). Beside this role, HLTF exhibits an ATP ATPase activity (Sheridan et al., 1995; Hayward- hydrolysis-dependent protein remodeling activity at Lester et al., 1996; MacKay et al., 2009). stalled replication fork: HLTF catalyzes the E3 ubiquitin ligase activity: clearance of roadblocks in replication fork restart The RING domain insures protein-protein (Achar et al., 2011). interactions in E3 ubiquitin ligases. It allows specific HLTF can also promote the intrusion of the newly targeting of the substrate proteins for transfer of synthesized strand, stalled by a damage, in the sister ubiquitin by the associated E2 ubiquitin ligase. The chromatid to bypass the lesion (Burkovics et al., HLTF RING domain is situated between helicase 2013). Both RING and helicase domains are critical domains III and IV and is strongly conserved in for this process (Blastyak et al., 2010). Studies on evolution. HLTF and its homologue SHPRH are the HLTF HIRAN domain revealed how HLTF functional orthologues of Rad5 in S. cerevisiae, recognizes a stalled replication fork and restarts it by which mediates the polyubiquitination of PCNA fork regression (Hishiki et al., 2015; Ikegaya et al., lysine 63 when damage is detected on the lagging 2015). Stalled replication forks contain a 3'-hydroxyl DNA strand during replication (Unk et al., 2008; group (3'-OH) on the nascent leading strand, which Motegi et al., 2008). The HLTF E3 ubiquitin ligase mimics a site of two unpaired nucleotides ("lesion"). activity was confirmed with a range of E2 ubiquitin HLTF specifically recognizes this "lesion" by its ligases (MacKay et al., 2009). HIRAN domain pocket in which (i) the two unpaired DNA repair: nucleotides are stuck between two tyrosines (Y72 The SNF2 domain is situated between the HLTF and Y93) and (ii) the 3'-OH single DNA (ssDNA) DBD and the first helicase domain. It is present in a end binds to an aspartate (D94) (Kile et al., 2015; large variety of proteins implicated in DNA repair, Tsutakawa et al., 2015). Fork reactivation is also recombination, chromatin remodelling and promoted via concerted mediation of TP53, POLI transcription (Eisen et al., 1995; Linder et al., 2004). (POLι), HLTF and ZRANB3 (Hampp et al., 2016). In addition, part of the HLTF DNA binding domain Isoforms of RUSH (rabbit HLTF) interact with a is conserved in SWI2/SNF2 proteins such as RING-finger binding protein (RFBP), which is a RAD5P: this domain was named HIRAN based on splice variant of the Type IV P-type ATPase, one of the HLTF alternatives names (HIP116) and ATP11B. This protein is a putative phospholipid the Rad5p N-terminal domain. HLTF is involved in pump, located in the inner nuclear membrane and the post replication DNA repair (Unk et al., 2008; interaction with the HLTF RING domain is Motegi et al., 2008). HLTF can complement the conserved in humans (Mansharamani et al., 2001; ultraviolet (UV) sensitivity of rad5- yeast cells, thus Hewetson et al., 2008). strongly supporting a role in postreplication DNA Homology repair (Unk et al., 2008). Hltf-deficient mouse embryonic fibroblasts show elevated chromosome SMARCA3 (chimpanzee: 99%; dog: 93%; cow: breaks and fusions after methyl methane sulfonate 91% identity) treatment (Motegi et al., 2008). In addition the HLTF RUSH-1-alpha and RUSH-1-beta (rabbit: 91% and protein interacts with PAXIP1 (PTIP) and RPA70, 90% identity)

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P113 (rat and mouse: 83% identity) Prognosis MGC131155 (Xenopus leavis: 63% identity) This cancer is very aggressive and with a poor RAD5B (Saccharomyces cerevisiae: 25, 7% prognosis. identity) Uterine cancer Implicated in HLTF promoter hypermethylation was found in 22% of uterine cancers, but it was more frequently Colorectal cancer methylated in cervical adenocarcinomas (43%) and HLTF promoter methylation is rare in normal colon in endometrial adenocarcinomas. tissue (3.0-10.2 %). However, it is increased in colon These findings suggest that HLTF promoter adenoma (25.7-68.5 %) and remains stable or hypermethylation may predispose to the slightly increased in invasive carcinomas (34.3-41.4 development of specific types of human uterine %), independently of tumor stage (reviewed in cancer (Kang et al., 2006). Dhont et al., 2015). Colorectal cancers with a highly HLTF immunodetection increased during the methylated panel of genes, including HLTF, are oncogenesis in cervical cancer (Capuillez et al., associated with the absence of lymph nodes 2011): cervix carcinomas (SCC, AD and AD in situ) metastasis and with a poorly differentiated histology exhibited the highest HLTF immunostaining. (Hibi et al., 2005 and 2006). HLTF promoter Truncated protein forms were detected in SCC (no hypermethylation alone was significantly less data about AD and AD in situ). No correlation with frequent in non-metastatic (Dukes's stages B and C) clinical data was presented in this study. In addition, than in metastatic (Duke's stage D) primary cancers Cho et al. (2011) showed HLTF overexpression in (reviewed in Dhont et al., 2015). recurrent cervical carcinoma following radiation treatment compared with patients with former Prognosis cervical cancer without recurrence; this might confer HLTF promoter hypermethylation alone or with a radiation resistance in cervical cancer, but the HLTF panel of other genes is an independent pejorative protein form expressed in these cases was not prognostic factor in colorectal cancer, associated determined. Ye et al. (2015) also showed that HLTF with a shorter survival and higher risk of disease mRNA was a target of MIR145, which is decreased recurrence. It also correlated with larger tumor size, in cervical cancers and is associated with radio- higher stage and grade, and metastatic disease sensitivity. Indeed, MIR145 and HLTF expression (reviewed in Dhont et al., 2015). levels were inversely correlated in radio-resistant Gastric carcinoma cervical cancers. The HLTF promoter hypermethylation has been Abnormal protein detected in approximately 20-55% of primary gastric In cervix cancer, truncated forms of HLTF proteins cancers (Hibi et al., 2003; Hamai et al., 2003; Kim et were detected. These forms result from an alternative al., 2006; Leung et al., 2003; Oue et al., 2006). For splicing of HLTF mRNA (Exons 19-22). patients with family histories HLTF gene silencing Renal cancer is probably an early stage of gastric carcinogenesis. HLTF mRNA expression has been studied in Experimental model of estrogen-induced different gastric carcinoma cell lines and Hamai et carcinogenesis in hamster. Early overexpression of al., 2003 have shown that the KATO-III cells present HLTF in tumor buds (Debauve et al., 2006). loss of HLTF expression associated with its Determination of human iris colour promoter methylation. A chromatin (blue/brown eye colour) immunoprecipitation assay revealed that the acetylation levels of histones H3 and H4 in the 5' See Sturm et al., 2008 and Sturm et al., 2009. CpG island of the HLTF gene were inversely Disease associated with DNA methylation status. These None findings support a model in which methyl-CpG- Cytogenetics binding proteins act as anchors on methylated DNA, The identified SNP (rs 12913832 T/C) in the OCA2 recruiting accessory proteins, such as HDAC, that intron 86 of the HERC2 locus serve as a target for contribute to build a repressive chromatin structure. the SWI/SNF family member HLTF. Esophageal squamous cell Hybrid/Mutated gene carcinoma (ESCC) None The HLTF promoter was found methylated in 1 case out of 40, suggesting that it is not a common target for epigenetic gene silencing in ESCC (Hibi et al., 2003).

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Figure 2. Model for the determination of the blue-brown eye colour based upon regulation of OCA2 (Sturm et al., 2009). Abnormal protein lesions (including 10 colloid nodules, 16 follicular None adenomas, 7 Hashimoto's thyroiditis, and 7 Grave's disease) and malignant lesions (including 17 Head and Neck Cancers papillary carcinomas and 12 follicular variant of HLTF expression was assessed by papillary carcinomas) were compared. immunohistochemistry followed by microscopy HLTF staining was strong and primarily located in computer-assisted quantification and nuclei in benign lesions, and it was weaker and immunodetection on western blots. shifted to the cytoplasm in malignant lesions. In HSCC, HLTF staining increased from tumor-free Interestingly, thyroid immune diseases (Hashimoto tissue to carcinoma, associated with a protein shift and Graves's diseases) harbored lower HLTF from the nucleus to the cytoplasm between dyplasias expression within the benign lesion group (Arcolia and carcinomas. et al., 2014). In LSCC, HLTF expression decreased from tumor- Disease free tissue to carcinomas, associated with a nucleo- Thyroid adenoma and carcinoma (papillary, cytoplasmic translocation in dyplasias and follicular, and anaplastic), Hashimoto's thyroiditis carcinomas (Capouillez et al., 2008 and 2009). and Grave's disease. Disease Prognosis Hypopharyngeal (HSCC) and Laryngeal Squamous HLTF was proposed as a biomarker in the Cell Carcinoma (LSCC) differential diagnosis of benign and malignant Prognosis thyroid lesions. In HSCC, HLTF detection is an independent prognostic marker of disease recurrence. To be noted In LSCC, there is a trend of a higher risk of recurrence in low-HLTF carcinoma. Note Abnormal protein Alternative splicing variants: Ref: Capouillez et In both HSCC and LSCC, truncated forms of HLTF al., 2009 proteins were detected. Exons 1 & 2 Exon 20 Intron 21 These forms result from an alternative splicing of

HLTF mRNA (Exons 19-22). Met1 + + - Thyroid Cancer HLTF expression was assessed in two independent Met1 ΔA + - + cohorts. In the first cohort (80 patients), HLTF expression Met1 ΔB + + + was compared among adenoma, papillary carcinoma, follicular carcinoma and anaplastic Met123 - + - carcinoma: adenomas presented strong nuclear HLTF immunostaining, whereas carcinomas Met123 ΔA - - + exhibited HLTF only in the cytoplasm. In the second cohort (69 patients), benign thyroid Met123 ΔB - + +

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Figure 3. Alternative splicing and encoded proteins of HLTF. For each HLTF protein form, the name, number of amino acids and the theoretical molecular weight (kDa) are indicated (left). Met1 is the first methionine, corresponding to the first translation start site, and Met123 is the methionine 123, corresponding to the alternative translation start site (exon 3). The protein domains are indicated as colored boxes. DBD (orange): DNA binding domain. SNF2 (blue): SNF2 domain. Yellow boxes from I to VI: Helicase/ATPase domains. RING (green): RING domain. The white flag "NLS" represents the nuclear localization signal (amino- acids KRRK at position 380 encoded by exons 10-11). Above each protein, the mRNA area of exons 19-22 is represented. This area is subjected to alternative splicing, resulting in protein forms truncated at the carboxyl-terminus. Exons and introns are represented as colored rectangles. The red crosses indicate the early stop codons, resulting from reading frameshifts (Dhont et al., 2015)

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