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“…Rewritten in the Skin”: Clues to Skin Biology and Aging from Inherited Disease

  • Raymond J. Monnat Jr
    Correspondence
    Department of Pathology and Genome Sciences, University of Washington, Box 357705, Seattle, Washington 91895-7705
    Affiliations
    Department of Pathology and Genome Sciences, University of Washington, Seattle, Washington, USA
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      The growing diversity of heritable skin diseases, a practical challenge to clinicians and dermato-nosologists alike, has nonetheless served as a rich source of insight into skin biology and disease mechanisms. I summarize below some key insights from the recent gene-driven phase of research on Werner syndrome, a heritable adult progeroid syndrome with prominent dermatologic features, constitutional genomic instability, and an elevated risk of cancer. I also indicate how new insights into skin biology, disease, and aging may come from unexpected sources.

      Abbreviations

      BS
      Bloom syndrome
      RTS
      Rothmund–Thomson syndrome
      WS
      Werner syndrome

      INTRODUCTION

      Werner syndrome (WS) is an autosomal recessive disease that first captured wide attention owing to its prominent premature aging (or progeroid) features. WS is also of considerable biomedical science interest in light of the pairing of these progeroid features with constitutional genomic instability and an elevated risk of many clinically important, age-dependent human diseases.
      The progeroid features of WS were first well described by
      • Werner O.
      On cataract in conjunction with scleroderma (translated by H. Hoehn).
      , who described a North German family of four siblings, aged 31–40 years, with short stature, prematurely gray hair, bilateral cataracts, atrophy of the extremities, hyperkeratosis, and scleroderma-like changes together with foot and ankle skin ulceration. He noted that one of the siblings, a 36-year-old man, gave “…the impression of extreme senility.” These observations were published as part of Werner’s doctoral thesis before his embarking on a career in a small North Sea village. Werner never again returned to study his syndrome (
      • Pehmoeller G.
      Memory of my father, Otto Werner.
      ).
      The term “Werner’s syndrome” was first used in a subsequent report of an additional patient who resembled the family members seen by Werner (
      • Oppenheimer B.S.
      • Kugel V.H.
      Werner's syndrome - a heredo-familial disorder with scleroderma, bilateral juvenile cataract, precocious graying of hair and endocrine stigmatization.
      ). This case report together with a more comprehensive study by Thannhauser of five additional patients (
      • Thannhauser S.J.
      Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two types of closely related hederofamilial atrophic dermatoses with juvenile cataracts and endocrine features; a critical study of five new cases.
      ) provided a detailed description of WS. WS was next “rediscovered” by colleagues at the University of Washington, who described three Japanese-American sisters with WS (one of whom is shown in Figure 1). Their analysis established the autosomal recessive inheritance of WS and delineated key differences between WS and normal aging (
      • Epstein C.J.
      • Martin G.M.
      • Schultz A.L.
      • et al.
      Werner's syndrome: A review of its symptoma-tology, natural history, pathologic features, genetics and relationship to the natural aging process.
      ).
      Figure thumbnail gr1
      Figure 1Clinical features and progression of Werner syndrome. Left photo panels are of a Japanese-American WS patient reported by
      • Epstein C.J.
      • Martin G.M.
      • Schultz A.L.
      • et al.
      Werner's syndrome: A review of its symptoma-tology, natural history, pathologic features, genetics and relationship to the natural aging process.
      , at ages 15 (left) and 48 (right) years. Right photo panels are of a Caucasian WS patient at ages ~13 (left) and 56 (right) years. Key clinical features of WS are present in both sets of photos, including the rounded face, sharp facial features, graying, thinning, and loss of scalp and eyebrow hair, and in Patient 2, right panel, thin, atrophic forearms and right elbow ulceration. Archival photos of patient 1, kindly provided by Drs George Martin and Nancy Hanson of the International Registry of Werner Syndrome, were digitized and restored by Alden Hackmann.
      They are used courtesy of Lippincott Williams & Wilkins. Photos of patient 2 were provided by Dr George Martin, and are used here courtesy of the patient’s spouse with informed consent of the patient, and of Elsevier Press where they were originally published in different form (
      • Martin G.M.
      Genetic modulation of senescent phenotypes in Homo sapiens.
      ).

      WS as a clinical entity

      The most consistent and earliest noted findings are premature graying and loss of hair together with bilateral cataracts, short stature, and progressive, scleroderma-like skin changes (Table 1;
      • Epstein C.J.
      • Martin G.M.
      • Schultz A.L.
      • et al.
      Werner's syndrome: A review of its symptoma-tology, natural history, pathologic features, genetics and relationship to the natural aging process.
      ;
      • Tollefsbol T.O.
      • Cohen H.J.
      Werner's sydrome: an underdiagnosed disorder resembling premature aging.
      ;
      • Goto M.
      Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing.
      ). Hair graying and loss begin in the second decade with the scalp and eyebrows, as do bilateral ocular cataracts. The short stature of WS patients reflects the absence of a pubertal growth spurt. Short stature together with progressive limb thinning, atrophy, and a stocky trunk give many patients a “cushingoid” appearance (see Figure 2 in
      • Goto M.
      Clinical characteristics of Werner syndrome and other premature aging syndromes: pattern of aging in progeroid syndromes.
      ).
      Table 1Diagnostic criteria of Werner syndrome
      CategoryWS signs and symptoms
      WS signs and symptoms are from the diagnostic criteria established by the International Registry of Werner Syndrome: www.wernersyndrome.org/registry/diagnostic.html, with additional discussion and application provided in Lauper et al. (2013).
      Cardinal1. Cataracts (bilateral)
      2. Scleroderma-like skin changes
      3. Short stature
      4. Parental consanguinity
      5. Premature graying and/or thinning of scalp hair
      Additional1. Diabetes mellitus
      2. Hypogonadism
      3. Osteoporosis
      4. Osteosclerosis (distal phalanges/fingers and/or toes)
      5. Soft tissue calcification
      6. Premature atherosclerosis
      7. Neoplasia
      8. Thin, high-pitched voice
      CategoryDiagnostic confidenceDiagnostic criteria
      DefiniteHigh confidenceAll cardinal signs + two additional signs OR confirmed pathogenic WRN mutations in both alleles
      ProbableHigh confidenceFirst three cardinal signs + any 2 others
      PossibleLow confidenceEither cataracts or dermatological changes + any 4 additional signs
      ExclusionExcludeSigns or symptoms before adolescence (except stature)
      1 WS signs and symptoms are from the diagnostic criteria established by the International Registry of Werner Syndrome: www.wernersyndrome.org/registry/diagnostic.html, with additional discussion and application provided in
      • Lauper J.M.
      • Krause A.
      • Vaughan T.L.
      • et al.
      Spectrum and risk of neoplasia in Werner syndrome: A systematic review.
      .
      The scleroderma-like skin changes of WS (
      • Thannhauser S.J.
      Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two types of closely related hederofamilial atrophic dermatoses with juvenile cataracts and endocrine features; a critical study of five new cases.
      ) consist of a mix of atrophic and proliferative changes: epidermal atrophy that includes skin appendages in conjunction with focal hyperkeratosis and basal hypermelanosis. Dermal subcutaneous atrophy is often found with dermal fibrosis underlying atrophic skin (
      • Thannhauser S.J.
      Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two types of closely related hederofamilial atrophic dermatoses with juvenile cataracts and endocrine features; a critical study of five new cases.
      ;
      • Epstein C.J.
      • Martin G.M.
      • Schultz A.L.
      • et al.
      Werner's syndrome: A review of its symptoma-tology, natural history, pathologic features, genetics and relationship to the natural aging process.
      ;
      • Goto M.
      Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing.
      ;
      • Hatamochi A.
      Dermatological features and collagen metabolism in Werner syndrome.
      ). These changes give skin a “tight, white, and shiny” appearance, with a progressive sharpening of facial features to give a “pinched”, “beaked”, or “bird-like” appearance (see Figure 3 in
      • Goto M.
      Clinical characteristics of Werner syndrome and other premature aging syndromes: pattern of aging in progeroid syndromes.
      ). The lower extremities, especially the feet, may be markedly deformed with ulceration and calcification of soft tissue and tendons (
      • Hatamochi A.
      Dermatological features and collagen metabolism in Werner syndrome.
      ).
      Many of these changes are readily apparent in patient photos taken in early adulthood and later in life (Figure 1). The progressive development of phenotype makes the diagnosis of WS challenging, especially in young adults. However, cardinal features are often present early, and they can be used together with molecular confirmation to confirm or exclude a diagnosis (Table 1;
      • Hisama F.M.
      • Kubisch C.
      • Martin G.M.
      • et al.
      Clinical utility gene card for: Werner Syndrome.
      ).

      RELATED RECQ HELICASE DEFICIENCY SYNDROMES

      The positional cloning of the WRN locus (
      • Yu C.E.
      • Oshima J.
      • Fu Y.H.
      • et al.
      Positional cloning of the Werner's syndrome gene.
      ) and other members of the RECQ helicase gene family led to the recognition of deeper links between WS and two additional genodermatoses: Bloom syndrome (BS;
      • Ellis N.A.
      • Groden J.
      • Ye T.Z.
      • et al.
      The Bloom's syndrome gene product is homologous to RecQ helicases.
      ) and Rothmund–Thomson syndrome (RTS;
      • Kitao S.
      • Shimamoto A.
      • Goto M.
      • et al.
      Mutations in RECQ4L cause a subset of cases of Rothmund-Thomson syndrome.
      ). BS patients display congenital short stature and a characteristic sun-sensitive “butterfly” rash across the bridge of the nose and cheeks that may involve hands and forearms (
      • Bloom D.
      Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs.
      ). Many patients display cellular and humoral immune deficits, an elevated risk of otitis media, pneumonia, and diabetes mellitus with reduced fertility. Cancer is the leading cause of premature death (
      • Bloom D.
      Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs.
      ;
      • German J.
      Bloom's syndrome: VIII. Review of clinical and genetic aspects.
      ,
      • German J.
      Bloom syndrome: a Mendelian prototype of somatic mutational disease.
      ,
      • German J.
      Bloom's syndrome: XX. The first 100 cancers.
      ).
      RTS was first described as a familial occurrence of skin changes with bilateral juvenile cataracts (
      • Rothmund A.
      Ueber cataracten in verbindung mit einer eigent mlichen hautdegeneration.
      ;
      • Thomson M.S.
      Poikiloderma congenitale.
      ;
      • Taylor W.B.
      Rothmund's syndrome–Thomson's syndrome: Congenital poikiloderma with and without juvenile cataracts. A review of the literature,report of a case, and discussion of the relationship of the two syndromes.
      ). A characteristic sun-sensitive rash with redness, swelling, and blistering appears in the first year of life, and it may involve the buttocks and extremities while sparing the chest, back, and abdomen. The rash may further develop variable pigmentation, telangiectasia, and focal atrophy. Hair, eyelashes, and eyebrows are often sparse or absent. Congenital short stature is common, although less severe than in BS. Developmental abnormalities include dysplastic, malformed, or absent bones, often in the hand or thumbs; delayed bone formation or bone density loss; and malformed, missing, or extra teeth. Cataracts have been documented in only a minority of contemporary RTS patients (
      • Wang L.L.
      • Levy M.L.
      • Lewis R.A.
      • et al.
      Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.
      ;
      • Larizza L.
      • Roversi G.
      • Volpi L.
      Rothmund-Thomson syndrome.
      ). Cancer risk is largely limited to osteosarcoma (
      • Wang L.L.
      • Gannavarapu A.
      • Kozinetz C.A.
      • et al.
      Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
      ;
      • Siitonen H.A.
      • Sotkasiira J.
      • Biervliet M.
      • et al.
      The mutation spectrum in RECQL4 diseases.
      ). Immunologic function appears intact, but fertility may be reduced. Additional diseases associated with RECQL4 mutations are RAPADILINO and Baller–Gerold syndromes. RAPADILINO syndrome patients have joint dislocations and patellar hypoplasia or aplasia, but lack skin changes. Baller–Gerold syndromes patients have craniosynostosis with radial aplasia, and RTS-like skin changes (
      • Siitonen H.A.
      • Kopra O.
      • Kaariainen H.
      • et al.
      Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases.
      ;
      • Van Maldergem L.
      • Siitonen H.A.
      • Jalkh N.
      • et al.
      Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene.
      ;
      • Siitonen H.A.
      • Sotkasiira J.
      • Biervliet M.
      • et al.
      The mutation spectrum in RECQL4 diseases.
      ). Life expectancy appears normal in the absence of cancer (
      • Wang L.L.
      • Levy M.L.
      • Lewis R.A.
      • et al.
      Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.
      ;
      • Larizza L.
      • Roversi G.
      • Volpi L.
      Rothmund-Thomson syndrome.
      ).

      ELEVATED ACQUIRED DISEASE RISK IN WS

      Many WS patients prematurely develop age-dependent diseases such as myocardial infarction and stroke; cancer; osteoporosis; diabetes mellitus; and hypogonadism. Cardiovascular disease and cancer are leading causes of premature death (
      • Goto M.
      Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing.
      ;
      • Goto M.
      • Ishikawa Y.
      • Sugimoto M.
      • et al.
      Werner syndrome: A changing pattern of clinical manifestations in Japan (1917–2008).
      ). The elevated risk of neoplasia is quite selective: two-thirds of neoplasms in WS patients were of six, not obviously related, tumor types: thyroid epithelial carcinomas, melanomas, meningiomas, soft tissue sarcomas, hematologic neoplasia, chiefly leukemias, and osteosarcoma (
      • Lauper J.M.
      • Monnat Jr, R.J.
      Diabetes mellitus and cancer in Werner syndrome.
      ;
      • Lauper J.M.
      • Krause A.
      • Vaughan T.L.
      • et al.
      Spectrum and risk of neoplasia in Werner syndrome: A systematic review.
      ;
      • Monnat Jr, R.J.
      Werner syndrome.
      ). Multiple neoplasms were common: 22% of 189 patients in our series had one to four concurrent or sequential neoplasms, often of unusual types or at unusual sites. For example, melanomas were almost exclusively less common variants: acral lentiginous melanomas arising on the palms, soles, or in nail beds, and mucosal melanomas arising in the nasal cavity or esophagus. Thyroid neoplasms, in a similar manner, were disproportionately less common follicular carcinomas (
      • Lauper J.M.
      • Krause A.
      • Vaughan T.L.
      • et al.
      Spectrum and risk of neoplasia in Werner syndrome: A systematic review.
      ). The excess risk of these specific neoplasms, estimated using a combination of standardized incidence ratio, proportional incidence ratio analyses, ranged from nearly 60-fold for melanoma to 1.5-fold for leukemia and preleukemic disorders (
      • Lauper J.M.
      • Krause A.
      • Vaughan T.L.
      • et al.
      Spectrum and risk of neoplasia in Werner syndrome: A systematic review.
      ). This spectrum of neoplasia overlaps with, but is distinct from, the neoplasms observed in BS and RTS (
      • German J.
      Bloom's syndrome: XX. The first 100 cancers.
      ;
      • Monnat Jr., R.J.
      Cancer pathogenesis in the human RecQ helicase deficiency syndromes.
      ;
      • Siitonen H.A.
      • Sotkasiira J.
      • Biervliet M.
      • et al.
      The mutation spectrum in RECQL4 diseases.
      ). BS is unusual among heritable cancer predispositions, as many different tumor types are involved (
      • German J.
      Bloom's syndrome: XX. The first 100 cancers.
      ;
      • Monnat Jr., R.J.
      Cancer pathogenesis in the human RecQ helicase deficiency syndromes.
      ). The cancer risk in the RTS-associated RECQL4 syndromes is, conversely, restricted largely to osteosarcoma and lymphoma (
      • Wang L.L.
      • Levy M.L.
      • Lewis R.A.
      • et al.
      Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.
      ,
      • Wang L.L.
      • Gannavarapu A.
      • Kozinetz C.A.
      • et al.
      Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
      ;
      • Siitonen H.A.
      • Sotkasiira J.
      • Biervliet M.
      • et al.
      The mutation spectrum in RECQL4 diseases.
      ).

      PHYSIOLOGIC ROLES OF RECQ HELICASES

      All of the human RECQ helicases hydrolyze ATP, unwind double-stranded DNA, and possess good DNA strand annealing activity. WRN alone possesses an additional, 3′ to 5′ exonuclease activity. Despite their common biochemical activities, the three disease-associated RECQ helicases have differing substrate preferences and different sets of protein partners (reviewed in
      • Bachrati C.Z.
      • Hickson I.D.
      RecQ helicases: suppressors of tumorigenesis and premature aging.
      ;
      • Brosh Jr., R.M.
      DNA helicases involved in DNA repair and their roles in cancer.
      ;
      • Croteau D.L.
      • Popuri V.
      • Opresko P.L.
      • et al.
      Human RecQ helicases in DNA repair, recombination, and replication.
      ;
      • Sidorova J.M.
      • Monnat Jr, R.J.
      Human RECQ helicases: roles in cancer, aging, and inherited disease.
      ). These biochemical data together with functional and cellular data begin to indicate how these seemingly similar proteins fill different physiologic “niches” in human cells and, by extension, how the loss of function of one RECQ protein may lead to distinct cellular and organismal phenotypes.
      Functional characterizations have identified distinct roles in specific RECQ helicase proteins in DNA replication. For example, RECQL4 and, to a lesser extent, RECQL bind replication origins and contribute to DNA replication initiation (
      • Thangavel S.
      • Mendoza-Maldonado R.
      • Tissino E.
      • et al.
      The human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation.
      ;
      • Xu X.
      • Rochette P.J.
      • Feyissa E.A.
      • et al.
      MCM10 mediates RECQ4 association with MCM2-7 helicase complex during DNA replication.
      ). Single-molecule DNA replication track analyses that we and others have performed revealed roles for BLM, WRN, and RECQL in replication fork rate maintenance and fork restart (
      • Sidorova J.M.
      • Li N.
      • Folch A.
      • et al.
      The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest.
      ;
      • Berti M.
      • Chaudhuri A.R.
      • Thangavel S.
      • et al.
      Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition.
      ;
      • Sidorova J.M.
      • Kehrli K.
      • Mao F.
      • et al.
      Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling.
      ). RECQL4 has an interesting additional role in mtDNA maintenance: it is coimported with TP53, and it appears to limit mtDNA damage in a replication-dependent manner (
      • Croteau D.L.
      • Rossi M.L.
      • Canugovi C.
      • et al.
      RECQL4 localizes to mitochondria and preserves mitochondrial DNA integrity.
      ;
      • De S.
      • Kumari J.
      • Mudgal R.
      • et al.
      RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress.
      ;
      • Gupta S.
      • De S.
      • Srivastava V.
      • et al.
      RECQL4 and p53 potentiate the activity of polymerase γ and maintain the integrity of the human mitochondrial genome.
      ).
      Several RECQ helicases also help maintain telomeres, although they again display apparent functional specialization. Telomeric DNA poses a dual challenge to the DNA replication machinery, as it is composed of repeated (the human telomeric repeat sequence is TTAGGG), GC-rich DNA organized into a unique chromatin “cap” at the ends of chromosomes (
      • Sfeir A.
      • Kosiyatrakul S.T.
      • Hockemeyer D.
      • et al.
      Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication.
      ). G-rich lagging strands may form G4 DNA quadruplex structures (
      • Maizels N.
      • Gray L.T.
      The G4 genome.
      ), which are good biochemical substrates for WRN and BLM. Only WRN helicase activity is required for complete replication of telomeric G-rich lagging strands, whereas cells lacking RECQL, RECQL4, or BLM also show telomere breakage and loss. It is unclear whether these effects are via a common mechanism (
      • Crabbe L.
      • Verdun R.E.
      • Haggblom C.I.
      • et al.
      Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.
      ,
      • Crabbe L.
      • Jauch A.
      • Naeger C.M.
      • et al.
      Telomere dysfunction as a cause of genomic instability in Werner syndrome.
      ;
      • Barefield C.
      • Karlseder J.
      The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures.
      ;
      • Ghosh A.K.
      • Rossi M.L.
      • Singh D.K.
      • et al.
      RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance.
      ;
      • Popuri V.
      • Hsu J.
      • Khadka P.
      • et al.
      Human RECQL1 participates in telomere maintenance.
      ). In contrast, WRN and BLM both participate in the recombination-mediated “alternative lengthening of telomeres” pathway used by many tumor cells to gain replicative immortality (
      • Mendez-Bermudez A.
      • Hidalgo-Bravo A.
      • Cotton V.E.
      • et al.
      The roles of WRN and BLM RecQ helicases in the alternative lengthening of telomeres.
      ). One phenomenon that is not yet well-understood is the sensitivity of WRN+ cells to telomere-homologous DNA oligonucleotides (“T-oligos”). The ability to respond to T-oligos may depend upon WRN exonuclease activity, and may have therapeutic potential in light of protective or deleterious responses in different cell types (
      • Eller M.S.
      • Liao X.
      • Liu S.
      • et al.
      A role for WRN in telomere-based DNA damage responses.
      ;
      • Gilchrest B.A.
      • Eller M.S.
      Cancer therapeutics: smart and smarter.
      ).
      All five of the human RECQ helicases also participate in DNA double-strand break repair by nonhomologous DNA end joining or homology-dependent recombination. WRN and RECQL4 participate in base excision repair, and RECQL5 may have an additional role in ssDNA break repair (reviewed in
      • Brosh Jr., R.M.
      DNA helicases involved in DNA repair and their roles in cancer.
      ;
      • Croteau D.L.
      • Popuri V.
      • Opresko P.L.
      • et al.
      Human RecQ helicases in DNA repair, recombination, and replication.
      ;
      • Sidorova J.M.
      • Monnat Jr, R.J.
      Human RECQ helicases: roles in cancer, aging, and inherited disease.
      ).

      “REWRITTEN IN THE SKIN”—RECQ HELICASES IN TRANSCRIPTION

      Previous analyses had suggested a role for the WRN and BLM RECQ helicases in transcription (
      • Kyng K.J.
      • May A.
      • Kolvraa S.
      • et al.
      Gene expression profiling in Werner syndrome closely resembles that of normal aging.
      ;
      • Johnson J.E.
      • Cao K.
      • Ryvkin P.
      • et al.
      Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential.
      ). To better understand this role, we analyzed gene and miRNA expression in mutation-typed WS and BS primary fibroblasts and in isogenic control primary fibroblasts depleted of the WRN or BLM protein. These analyses identified 3,000 genes and dozens of miRNAs whose expression was significantly altered by the loss of WRN and BLM function. Among the subset (-25%) of genes altered in both WS and BS cells, a surprisingly high fraction (>90%) had expression altered in the same direction (
      • Nguyen G.H.
      • Tang W.
      • Robles A.I.
      • et al.
      Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs.
      ). Many WRN- and BLM-responsive downregulated genes contained G quadruplex (G4) DNA motifs in their 5′ ends, providing strong evidence that G4 DNA structures are physiologic, as well as biochemical, substrates for WRN and BLM.
      The genes and miRNAs altered in WS and/or BS cells have important roles in pathways that drive cell growth, proliferation, death, and survival. BS patient cells had gene expression patterns predicted to alter DNA replication recombination and repair, as well as immune function and tumorigenic/DNA damage signaling. These make good sense in light of our understanding of the biochemical, cellular, and organismal phenotype of BS (
      • Nguyen G.H.
      • Tang W.
      • Robles A.I.
      • et al.
      Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs.
      ; Tang, Robles et. al., in preparation). WS appears more complex, and thus intriguing. One remarkable—and as yet not fully understood—finding in WS cells was coordinate upregulation of nearly all of the cytoplasmic tRNA synthestase (ARS) and synthetase-associated interacting protein (AIMP) genes (
      • Park S.G.
      • Choi E.-C.
      • Kim S.
      Aminoacyl-tRNA synthetase–interacting multifunctional proteins (AIMPs): A triad for cellular homeostasis.
      ;
      • Kim S.
      • You S.
      • Hwang D.
      Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping.
      ;
      • Wallen R.C.
      • Antonellis A.
      To charge or not to charge: mechanistic insights into neuropathy-associated tRNA synthetase mutations.
      ;
      • Yao P.
      • Fox P.L.
      Aminoacyl-tRNA synthetases in medicine and disease.
      ).
      The mechanism of ARS/AIMP upregulation is not yet understood but may include MYC, which can alter and in turn be modulated by ARSs (
      • Shi Y.
      • Xu X.
      • Zhang Q.
      • et al.
      tRNA synthetase counteracts c-Myc to develop functional vasculature.
      ) while driving expression of WRN and telomerase (
      • Grandori C.
      • Wu K.J.
      • Fernandez P.
      • et al.
      Werner syndrome protein limits MYC-induced cellular senescence.
      ). ARS and AIMP overexpression in WS could perturb protein homeostasis by altering global protein turnover and/or translational fidelity (
      • Lee J.Y.
      • Kim D.G.
      • Kim B.-G.
      • et al.
      Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress.
      ;
      • Wolff S.
      • Weissman Jonathan S.
      • Dillin A.
      Differential scales of protein quality control.
      ). Altered tRNA charging could affect the balance between mitochondrial and nuclear protein synthesis to promote mitochondrial dysfunction and oxidative stress (
      • Jovaisaite V.
      • Auwerx J.
      The mitochondrial unfolded protein response-synchronizing genomes.
      ). It could also drive disease pathogenesis via the growing list of ARS/AIMP “noncanonical” functions that modulate disease-related metabolic, developmental, angiogenic, tumorigenic, immune, and inflammatory pathways (
      • Guo M.
      • Schimmel P.
      Essential nontranslational functions of tRNA synthetases.
      ;
      • Son S.
      • Park M.
      • Kim S.
      Extracellular activities of aminoacyl-tRNA synthetases: new mediators for cell–cell communication.
      ). All of these areas are ripe for further exploration using a combination of new genomic and proteomic approaches.

      THE ORIGINS OF PHENOTYPE

      The biochemical and cellular specializations of the individual RECQ helicases outlined above begin to indicate how the loss of function of a single RECQ protein may lead to specific RECQ deficiency syndromes and their associated disease risks. As noted above, RECQ-deficient cells display cell proliferation defects in conjunction with genomic instability (
      • Martin G.M.
      • Sprague C.A.
      • Epstein C.J.
      Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype.
      ;
      • Warren S.T.
      • Schultz R.A.
      • Cc Chang
      • et al.
      Elevated spontaneous mutation rate in Bloom syndrome fibroblasts.
      ;
      • Dhillon K.K.
      • Sidorova J.
      • Saintigny Y.
      • et al.
      Functional role of the Werner syndrome RecQ helicase in human fibroblasts.
      ;
      • Sharma S.
      • Stumpo D.J.
      • Balajee A.S.
      • et al.
      RECQL, a Member of the RecQ Family of DNA Helicases, Suppresses Chromosomal Instability.
      ;
      • Thangavel S.
      • Mendoza-Maldonado R.
      • Tissino E.
      • et al.
      The human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation.
      ;
      • Mao F.J.
      • Sidorova J.M.
      • Lauper J.M.
      • et al.
      The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage.
      ;
      • Sidorova J.M.
      • Kehrli K.
      • Mao F.
      • et al.
      Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling.
      ). These cellular defects in turn are likely part of the explanation for why BS and RTS patients are often small, although proportionately developed. BLM or RECQL4 loss can both interfere with DNA replication and impair cell production throughout development. Despite this, development appears to be largely normal in both syndromes, and it responds by proportionately scaling output (the fetus) to reflect inadequate substrate (cells). This proportional dwarfing is particularly striking in BS, where patients are born and often remain at or below the 5th percentile for height and weight (
      • Keller C.
      • Keller K.R.
      • Shew S.B.
      • et al.
      Growth deficiency and malnutrition in Bloom syndrome.
      ).
      The progressive development of progeroid features in WS only after development is largely complete may reflect the starkly different outcome of replication arrest, which leads to high levels of cell death in BS, although not in WS, cells (
      • Mao F.J.
      • Sidorova J.M.
      • Lauper J.M.
      • et al.
      The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage.
      ;
      • Sidorova J.M.
      • Kehrli K.
      • Mao F.
      • et al.
      Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling.
      ). WRN loss, in contrast, has a more profound effect on transcription than does BLM loss, and thus may have a correspondingly more prominent role in transcription and tissue maintenance (see above). Disrupted DNA metabolism in WS patient cells could drive the progressive accumulation of mutant and senescent cells in many tissues, with acquisition of a senescence-associated secretory phenotype that could in turn promote the elevated risk of many clinically important age-associated diseases (
      • Campisi J.
      Aging, cellular senescence, and cancer.
      ). Cellular senescence in the RECQ helicase syndromes may have one modest silver lining: it is an effective, albeit nonspecific, tumor-suppressive mechanism (
      • Adda di Fagagna F.
      Living on a break: cellular senescence as a DNA-damage response.
      ;
      • Collado M.
      • Serrano M.
      Senescence in tumours: evidence from mice and humans.
      ). Altered RECQ expression, as opposed to mutation, may be frequent in many tumor types (
      • Lao V.V.
      • Welcsh P.
      • Luo Y.
      • et al.
      Altered RECQ helicase expression in sporadic primary colorectal cancers.
      ). However, the previous suggestion that these changes may be largely methylation-driven (
      • Agrelo R.
      • Cheng W.H.
      • Setien F.
      • et al.
      Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer.
      ) has not been consistent enough in our hands to serve as a reliable marker for altered WRN expression in tumors (
      • Lao V.V.
      • Welcsh P.
      • Luo Y.
      • et al.
      Altered RECQ helicase expression in sporadic primary colorectal cancers.
      ).
      More systematic collection of patient data, longitudinal study of patients, and the collection and distribution of well-characterized clinical samples should all aid our understanding of the RECQ deficiency syndromes. We also have a growing range of options to capture and analyze patient-derived cells and cell lines, including improved short-term primary culture, organoid culture, and the generation of cell lines and iPS cells (
      • Martin G.M.
      • Sprague C.A.
      • Epstein C.J.
      Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype.
      ;
      • Wyllie F.S.
      • Jones C.J.
      • Skinner J.W.
      • et al.
      Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.
      ;
      • Cheung H.-H.
      • Liu X.
      • Canterel-Thouennon L.
      • et al.
      Telomerase protects Werner syndrome lineage-specific stem cells from premature aging.
      ;
      • Shimamoto A.
      • Kagawa H.
      • Zensho K.
      • et al.
      Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture.
      ). These analyses and materials have the potential to identify genetic and environmental modifiers of disease progression and acquired disease risk.

      NEW CLUES TO SKIN BIOLOGY, DISEASE, AND THERAPY

      The above analyses emphasize the complexity of disease pathogenesis in even “simple” monogenic genetic diseases such as WS. They also emphasize how new insights into disease pathogenesis from rare heritable diseases may improve our understanding of skin biology while identifying potential new therapies. One example comes from another skin disease, recessive dystrophic epidemolysis bullosa. Recessive dystrophic epidemolysis bullosa results from COL7A1 mutations leading to loss of Type VII collagen, a marked reduction in anchoring fibrils, and extreme skin fragility with loss and scarring (
      • Tolar J.
      • Wagner J.E.
      Allogeneic blood and bone marrow cells for the treatment of severe epidermolysis bullosa: repair of the extracellular matrix.
      ).
      The potential for genetic therapies of epidermolysis bullosa and a handful of other heritable diseases was emphasized over two decades ago by the identification of patients who had undergone spontaneous reversion of causative mutations with partial or full correction of disease-specific defects in skin, blood, lymphoid, or liver (
      • Hirschhorn R.
      In vivo reversion to normal of inherited mutations in humans.
      ). A deeper understanding of the role of Type VII collagen in skin (
      • Tolar J.
      • Wagner J.E.
      Allogeneic blood and bone marrow cells for the treatment of severe epidermolysis bullosa: repair of the extracellular matrix.
      ) had led to a diversity of therapeutic approaches: complementation (
      GENEGRAFT
      Phase I/II ex vivo gene therapy clinical trial for recessive dystrophic epidermolysis bullosa using skin equivalent grafts genetically corrected with a COL7A1-encoding SIN retroviral vector (GENEGRAFT).
      ) or targeted correction of causative COL7A1 mutations in epidermal cells (
      • Sebastiano V.
      • Zhen H.H.
      • Haddad B.
      • et al.
      Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa.
      ); the use of patient-derived, mutation-reverted keratinocytes (
      • Tolar J.
      • McGrath J.A.
      • Xia L.
      • et al.
      Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa.
      ); and the repair in trans of anchoring fibrils using allogeneic fibroblasts (
      • Venugopal S.S.
      • Yan W.
      • Frew J.W.
      • et al.
      A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa.
      ), mutation-corrected, iPS-derived fibroblasts (
      • Wenzel D.
      • Bayerl J.
      • Nyström A.
      • et al.
      Genetically corrected iPSCs as cell therapy for recessive dystrophic epidermolysis bullosa.
      ), or bone marrow transplantation (
      • Wagner J.E.
      • Ishida-Yamamoto A.
      • McGrath J.A.
      • et al.
      Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.
      ;
      • Tolar J.
      • Wagner J.E.
      Allogeneic blood and bone marrow cells for the treatment of severe epidermolysis bullosa: repair of the extracellular matrix.
      ;). Repair in trans may be a viable option for dealing with the scleroderma-like skin changes seen in WS, as might aminoglycoside suppression of WRN missense mutations, a strategy that has been used in recessive dystrophic epidemolysis bullosa (
      • Cogan J.
      • Weinstein J.
      • Wang X.
      • et al.
      Aminoglycosides restore full-length Type VII collagen by overcoming premature termination codons: therapeutic implications for dystrophic epidermolysis bullosa.
      ).
      Another unusual example of where we may find new clues to treating heritable or acquired skin disease, as well as age-associated changes, comes from comparative genetics, more specifically the African spiny mice Acomys kempi and Acomys percivali. Acomys mice have the remarkable ability to shed–and then regenerate without scarring–large segments of skin, and may have evolved this ability to escape predators (
      • Seifert A.W.
      • Kiama S.G.
      • Seifert M.G.
      • et al.
      Skin shedding and tissue regeneration in African spiny mice (Acomys).
      ). Although scarless wound healing also occurs in humans, it is largely restricted to the fetus (
      • Yates C.C.
      • Hebda P.
      • Wells A.
      Skin wound healing and scarring: fetal wounds and regenerative restitution.
      ). Acomys mice, in contrast, are able to continuously regenerate skin without scarring in the face of injury, inflammation, and infection. Understanding the mechanistic basis for this remarkable example of epimorphic regeneration may identify new ways to maintain or rejuvenate skin, and to help individuals with injuries that lead to disfiguring scarring. Nature undoubtedly holds more examples of remarkable cutaneous biology. Finding these and turning them to good use will require imagination, together with a willingness to look—and think—a bit beyond our usual comfort zone.

      ACKNOWLEDGMENTS

      Work in the author’s lab has been supported by the US National Institutes on Aging, Cancer and Environmental Health Sciences and by the Nippon Boehringer Ingelheim Virtual Research Institute of Aging. I thank the many individuals who have contributed to the basic science of RECQ helicases, and patients, families, and clinicians for their friendship, generosity, and support. The preparation of this manuscript was supported in part by US NIH NCI Award CA77852 to the author, and Montagna Symposium on the Biology of Skin NIAMS/NIA award R13-AR009431-48 to M. Kulesz-Martin.

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