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ATRX and DAXX: Mechanisms and Mutations Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press ATRX and DAXX: Mechanisms and Mutations Michael A. Dyer,1 Zulekha A. Qadeer,2,3 David Valle-Garcia,2 and Emily Bernstein2,3 1Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 2Departments of Oncological Sciences and Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York 10029 3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Correspondence: [email protected]; [email protected] Recent genome sequencing efforts in a variety of cancers have revealed mutations and/or structural alterations in ATRX and DAXX, which together encode a complex that deposits histone variant H3.3 into repetitive heterochromatin. These regions include retrotranspo- sons, pericentric heterochromatin, and telomeres, the latter of which show deregulation in ATRX/DAXX-mutant tumors. Interestingly, ATRX and DAXX mutations are often found in pediatric tumors, suggesting a particular developmental context in which these mutations drive disease. Here we review the functions of ATRX and DAXX in chromatin regulation as well as their potential contributions to tumorigenesis. We place emphasis on the chromatin remodeler ATRX, which is mutated in the developmental disorder for which it is named, a-thalassemia, mental retardation, X-linked syndrome, and at high frequency in a number of adult and pediatric tumors. ecent whole-genome and exome sequencing Given that ATRX and DAXX form a histone Refforts across a wide spectrum of cancers chaperone complexthatdeposits histonevariant have unexpectedly revealed chromatin remod- H3.3 into specific genomic regions, it is intrigu- eling-encoding genes as being frequently altered ing that mutations in the histone as well as (Jiao et al. 2011; Schwartzentruber et al. 2012; its chaperone complex have been identified www.perspectivesinmedicine.org Cheung and Dyer 2013; Helming et al. 2014). (Schwartzentruber et al. 2012). Although cer- The ATRX gene, which encodes a SWI/SNF- tain H3.3mutationsappear tobeassociatedwith like chromatin remodeling protein, is frequent- altered Polycomb repressive complex 2 (PRC2) ly mutated in a variety of tumors, including activity (e.g., H3.3K27M) (Bender et al. 2013; adult lower-grade gliomas, pediatric glioblasto- Chan et al. 2013; Lewis et al. 2013; Funato et al. ma multiforme, pediatric adrenocortical carci- 2014), the mechanisms by which ATRX and noma, osteosarcoma, and neuroblastoma (Table DAXX mutations promote oncogenesis may be 1). Some, but not all, of these cancers also har- distinct from those elicited by H3.3 mutation. bor DAXX and/or H3F3A (H3.3) mutations Given the identification of ATRX and DAXX (Schwartzentruber et al. 2012; Wu et al. 2012). mutations in cancer, these factors have received Editors: Scott A. Armstrong, Steven Henikoff, and Christopher R. Vakoc Additional Perspectives on Chromatin Deregulation in Cancer available at www.perspectivesinmedicine.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a026567 Cite this article as Cold Spring Harb Perspect Med 2017;7:a026567 1 Downloaded from www.perspectivesinmedicine.org http://perspectivesinmedicine.cshlp.org/ M.A. Dyer et al. 2 Table 1. ATRX alterations identified in human cancers Co-occurrence of Frequency ALT DAXX/H3.3 Disease (%) Type of alteration Age group association mutations References Whole-genome and exome studies PanNets 19 Deletions, point Adult Yes Yes Heaphy et al. 2011; Jiao et al. 2011 LGG 42 Indels, point Adult Yes No Kannan et al. 2012; Johnson et al. 2014; TCGA 2015 onSeptember23,2021-PublishedbyColdSpringHarborLaboratory GBM 29/16 Indels, point Pediatric/adult Yes Yes/no Liu et al. 2012b; Schwartzentruber et al. 2012 Press DIPG 8 Point Pediatric N/AYes/no Khuong-Quang et al. 2012; Wu et al. 2014 Cite this article as NB 8/28 Indels, point, Pediatric/ Yes No Cheung et al. 2012; Molenaar et al. 2012; Pugh et al. 2013; in-frame fusions adolescent Peifer et al. 2015; Valentijn et al. 2015 OS 29 Indels, point, Pediatric/ Yes No Chen et al. 2014 in-frame fusions adolescent Adrenocortical 32 Indels, point Pediatric/ Yes Yes Assie´ et al. 2014; Pinto et al. 2015 tumors adolescent Cold Spring Harb Perspect Med Disease Frequency (%) Type of alteration Age group ALTassociation References mRNA/protein studies Melanoma N/A Transcriptional down-regulation, protein loss Adult N/A Liau et al. 2015b Leiomyosarcoma 33 Protein loss Adult Yes Liau et al. 2015c Angiosarcoma 18 Protein loss Adult Yes Liau et al. 2015a Liposarcoma 29 Protein loss Adult Yes Lee et al. 2015 Soft tissue sarcoma 13 Protein loss Adult Yes Liau et al. 2015a,b,c PanNets, Pancreatic neuroendocrine tumors; LGG, low-grade glioma; GBM, glioblastoma multiforme; DIPG, diffuse intrinsic pontine glioma; NB, neuroblastoma; OS, osteosarcoma; 2017;7:a026567 ALT, alternative lengthening of telomeres; N/A, not applicable. Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press ATRX/DAXX in Cancer renewed attention, particularly in the field of the type of mutations involved and their clini- pediatric oncology. To date, however, their role cal severity. For example, mutations in the ami- in promoting pathogenesis in both adult and no-terminal ADD (ATRX-DNTM3-DNMT3L) pediatric tumors remains unclear. Here we re- domain produce more severe psychomotor view the functions of the chromatin remodeler phenotypes than do mutations in the carboxy- ATRX and the histone chaperone DAXX in the terminal helicase domain (Badens et al. context of cellular biology, development, and 2006a). Interestingly, ATRX syndrome muta- disease. tions almost exclusively lie in either of these two domains (Fig. 1A). ATRX’s helicase domain has DNA translocase activity via ATP-depen- ATRX SYNDROME dent hydrolysis (Xue et al. 2003; Mitson et al. ATRX was first discovered through efforts to 2011). In fact, inactivating mutations in this identify the genetic lesion that contributes to domain results in translocase defects, and one the a-thalassemia, mental retardation, X-linked particular disease-causing mutation even un- (ATRX) syndrome (Gibbons et al. 2003). Pa- couples ATP hydrolysis from DNA binding tients are characterized during early childhood (Mitson et al. 2011). The ADD domain con- by distinctive craniofacial features, significant tains a GATA-like domain and a PHD (plant developmental delays, genital anomalies and homeodomain) finger, which together recog- sterility, microcephaly, and severe intellectual nize H3K9me3 when unmethylated at H3K4 disabilities (Gibbons et al. 2012). Coupled to (Dhayalan et al. 2011; Eustermann et al. 2011; these features, patients with ATRX syndrome Iwase et al. 2011). Interestingly, a nonsense mu- also present with varying degrees of anemia tation at residue 37 of ATRX is associated with caused by a-thalassemia, a condition caused a milder phenotype than that associated with by deficient a-globin expression (Gibbons missense mutations in the ADD and helicase et al. 2008). Consistent with a recessive X-linked domains (Guerrini et al. 2000). The nonsense inheritance pattern, ATRX syndrome is pre- mutation at residue 37 is spliced out of a subset dominant in males. However, there are rare re- of transcripts, which partially restores ATRX ports of ATRX syndrome in 46XX heterozygous protein function. Indeed, it has been proposed females, which show an uneven pattern of X- that virtually all mutations in patients with inactivation that favors the expression of the ATRX syndrome represent hypomorphs caused mutant allele (Badens et al. 2006b). by protein destabilizing effects of the muta- Importantly, mutations in ATRX are the tions (Gibbons et al. 2008). Because mutations only genetic lesions that cause ATRX syndrome in numerous cancers occur outside of the ADD www.perspectivesinmedicine.org (Gibbons et al. 2008). This suggests that ATRX and helicase domains and span widely across is essential for diverse developmental processes the ATRX coding region (Fig. 1), they have across the ectodermal (neural crest and central been proposed to be loss-of-function mutations nervous system [CNS]), mesodermal (bone (Watson et al. 2015). Consequently, ATRX syn- and erythroid lineage), and endodermal (geni- drome mutations may shed light on our under- talia) lineages. Interestingly, mutations in genes standing of somatic ATRX mutations in cancer. that encode proteins that interact with ATRX, such as DAXX, have not been identified in pa- MOUSE MODELS OF ATRX DEFICIENCY tients with ATRX syndrome. Moreover, ATRX patients do not have an increased incidence of Consistent with the hypothesis that ATRX is cancer. Taken together, ATRX plays a unique required for embryonic development, Atrx- role in development and raises questions about null mice die at E9.5 (Garrick et al. 2006). More- tissue specificity, as well as its role in promoting over, conditional inactivation of Atrx in the cancer. developing forebrain results in perinatal lethal- Considering the monogenic origins of ity. The frontal cortex, subiculum, and hippo- ATRX syndrome, it is important to identify campus are reduced in size, and the dentate Cite this article as Cold Spring Harb Perspect Med 2017;7:a026567 3 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press M.A. Dyer et al. A ATRX syndrome mutation distribution HP1α ADD EZH2 interacting Daxx interacting SNF2_N MacroH2A1 interacting domain 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 B 9 GBM, LGG, and NB mutation distribution 251 Mutations 8 Missense: 134 (53%) Synonymous: 30 (12%) 7 Truncating: 84 (33%) Splice-site: 1 (0%) 6 Other: 2 (1%) 5 4 No. of mutations of No. 3 2 1 0 ADD SNF2_N 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 Deletions Figure 1. Mutations identified in ATRX syndrome and a subset of cancers. (A) Schematic summarizing that the mutations identified in patients with ATRX syndrome are concentrated in the ADD and SNF2_N helicase domains.
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