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1.
Mol Cell ; 80(6): 996-1012.e9, 2020 12 17.
Article in English | MEDLINE | ID: mdl-33147438

ABSTRACT

Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.


Subject(s)
Alcohol Dehydrogenase/genetics , Aldehyde Dehydrogenase, Mitochondrial/genetics , Formaldehyde/blood , Leukemia/genetics , Adolescent , Aldehydes/blood , Animals , Child , Child, Preschool , DNA Adducts/genetics , DNA Damage/drug effects , DNA Repair/drug effects , Female , Formaldehyde/toxicity , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Humans , Infant , Leukemia/blood , Leukemia/pathology , Male , Mice , Mutation/genetics , Substrate Specificity
2.
Nature ; 574(7777): 249-253, 2019 10.
Article in English | MEDLINE | ID: mdl-31578523

ABSTRACT

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.


Subject(s)
Cell Differentiation , Epidermal Cells/cytology , Epidermis/physiology , Interferon Regulatory Factors/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Abnormalities, Multiple/genetics , Animals , Cleft Lip/genetics , Cleft Palate/genetics , Cysts/genetics , Embryo, Mammalian/cytology , Embryo, Mammalian/embryology , Embryo, Mammalian/metabolism , Epidermal Cells/metabolism , Epidermis/embryology , Eye Abnormalities/genetics , Female , Fingers/abnormalities , Gene Expression Regulation , Interferon Regulatory Factors/deficiency , Interferon Regulatory Factors/genetics , Knee/abnormalities , Knee Joint/abnormalities , Lip/abnormalities , Lipid Metabolism/genetics , Lower Extremity Deformities, Congenital/genetics , Male , Mice , Mice, Inbred C57BL , Phosphorylation , Phosphoserine/metabolism , Protein Serine-Threonine Kinases/genetics , Syndactyly/genetics , Urogenital Abnormalities/genetics
3.
Structure ; 26(5): 767-777.e5, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29706531

ABSTRACT

Receptor-interacting protein kinase 4 (RIPK4) is a highly conserved regulator of epidermal differentiation. Members of the RIPK family possess a common kinase domain as well as unique accessory domains that likely dictate subcellular localization and substrate preferences. Mutations in human RIPK4 manifest as Bartsocas-Papas syndrome (BPS), a genetic disorder characterized by severe craniofacial and limb abnormalities. We describe the structure of the murine Ripk4 (MmRipk4) kinase domain, in ATP- and inhibitor-bound forms. The crystallographic dimer of MmRipk4 is similar to those of RIPK2 and BRAF, and we show that the intact dimeric entity is required for MmRipk4 catalytic activity through a series of engineered mutations and cell-based assays. We also assess the impact of BPS mutations on protein structure and activity to elucidate the molecular origins of the disease.


Subject(s)
Adenosine Triphosphate/metabolism , Mutation , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Animals , Catalytic Domain , Crystallography, X-Ray , Enzyme Activation , Mice , Models, Molecular , Protein Conformation , Protein Multimerization , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins B-raf/chemistry , Receptor-Interacting Protein Serine-Threonine Kinase 2/chemistry
4.
Mol Cell ; 55(6): 807-817, 2014 Sep 18.
Article in English | MEDLINE | ID: mdl-25155611

ABSTRACT

Maternal metabolism provides essential nutrients to enable embryonic development. However, both mother and embryo produce reactive metabolites that can damage DNA. Here we discover how the embryo is protected from these genotoxins. Pregnant mice lacking Aldh2, a key enzyme that detoxifies reactive aldehydes, cannot support the development of embryos lacking the Fanconi anemia DNA repair pathway gene Fanca. Remarkably, transferring Aldh2(-/-)Fanca(-/-) embryos into wild-type mothers suppresses developmental defects and rescues embryonic lethality. These rescued neonates have severely depleted hematopoietic stem and progenitor cells, indicating that despite intact maternal aldehyde catabolism, fetal Aldh2 is essential for hematopoiesis. Hence, maternal and fetal aldehyde detoxification protects the developing embryo from DNA damage. Failure of this genome preservation mechanism might explain why birth defects and bone marrow failure occur in Fanconi anemia, and may have implications for fetal well-being in the many women in Southeast Asia that are genetically deficient in ALDH2.


Subject(s)
Acetaldehyde/metabolism , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase/metabolism , Embryo, Mammalian/metabolism , Ethanol/toxicity , Fanconi Anemia Complementation Group A Protein/genetics , Fanconi Anemia/pathology , Acetaldehyde/toxicity , Aldehyde Dehydrogenase 1 Family , Aldehyde Dehydrogenase, Mitochondrial , Animals , Animals, Newborn , DNA Damage , Disease Models, Animal , Embryo, Mammalian/embryology , Female , Genome , Hematopoietic Stem Cells/metabolism , Humans , Isoenzymes/genetics , Isoenzymes/metabolism , Mice , Mice, Inbred C57BL , Pregnancy , Retinal Dehydrogenase/genetics , Retinal Dehydrogenase/metabolism
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