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Hyun-min Kim - One of the best experts on this subject based on the ideXlab platform.
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Histone Demethylase amx 1 is necessary for proper sensitivity to interstrand crosslink dna damage
PLOS Genetics, 2021Co-Authors: Xiaojuan Zhang, Monica P. Colaiácovo, Sara E Beesesims, Sisi Tian, Jingjie Chen, Nara Shin, Hyun-min KimAbstract:Histone methylation is dynamically regulated to shape the epigenome and adjust central nuclear processes including transcription, cell cycle control and DNA repair. Lysine-specific Histone Demethylase 2 (LSD2) has been implicated in multiple types of human cancers. However, its functions remain poorly understood. This study investigated the Histone Demethylase LSD2 homolog AMX-1 in C. elegans and uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair. AMX-1 is a Histone Demethylase and mainly localizes to embryonic cells, the mitotic gut and sheath cells. Lack of AMX-1 expression resulted in embryonic lethality, a decreased brood size and disorganized premeiotic tip germline nuclei. Expression of AMX-1 and of the Histone H3K4 Demethylase SPR-5 is reciprocally up-regulated upon lack of each other and the mutants show increased H3K4me2 levels in the germline, indicating that AMX-1 and SPR-5 regulate H3K4me2 demethylation. Loss of AMX-1 function activates the CHK-1 kinase acting downstream of ATR and leads to the accumulation of RAD-51 foci and increased DNA damage-dependent apoptosis in the germline. AMX-1 is required for the proper expression of mismatch repair component MutL/MLH-1 and sensitivity against ICLs. Interestingly, formation of ICLs lead to ubiquitination-dependent subcellular relocalization of AMX-1. Taken together, our data suggest that AMX-1 functions in ICL repair in the germline.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone methylation levels and interact with the Histone Demethylase lsd1 spr 5 in caenorhabditis elegans
Genetics, 2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone Demethylase LSD1 was originally discovered by removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1). Several studies suggest that LSD1 plays roles in meiosis as well as in the epigenetic regulation of fertility given that, in its absence, there is evidence of a progressive accumulation of H3K4me2 and increased sterility through generations. In addition to the progressive sterility phenotype observed in the mutants, growing evidence for the importance of Histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone methylation is involved in DNA damage repair, and only a few studies have focused on the roles of Histone Demethylases in germline maintenance. Here, we show that the Histone Demethylase LSD1/CeSPR-5 interacts with the Fanconi anemia (FA) protein FANCM/CeFNCM-1 using biochemical, cytological, and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S phase-checkpoint activation, and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5, suggesting coordination between this Histone Demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance, regardless of the presence of replication stress. Our study reveals a connection between FA and epigenetic maintenance and therefore provides new mechanistic insight into the regulation of Histone methylation in DNA repair.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone methylation levels and interact with the Histone Demethylase lsd1 spr 5 in c elegans
bioRxiv, 2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone Demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of Histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone methylation is involved in DNA damage repair and only a few studies have been focused on the roles of Histone Demethylases in germline maintenance. Here, we show that the Histone Demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this Histone Demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of Histone methylation in DNA repair.
Monica P. Colaiácovo - One of the best experts on this subject based on the ideXlab platform.
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Histone Demethylase amx 1 is necessary for proper sensitivity to interstrand crosslink dna damage
PLOS Genetics, 2021Co-Authors: Xiaojuan Zhang, Monica P. Colaiácovo, Sara E Beesesims, Sisi Tian, Jingjie Chen, Nara Shin, Hyun-min KimAbstract:Histone methylation is dynamically regulated to shape the epigenome and adjust central nuclear processes including transcription, cell cycle control and DNA repair. Lysine-specific Histone Demethylase 2 (LSD2) has been implicated in multiple types of human cancers. However, its functions remain poorly understood. This study investigated the Histone Demethylase LSD2 homolog AMX-1 in C. elegans and uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair. AMX-1 is a Histone Demethylase and mainly localizes to embryonic cells, the mitotic gut and sheath cells. Lack of AMX-1 expression resulted in embryonic lethality, a decreased brood size and disorganized premeiotic tip germline nuclei. Expression of AMX-1 and of the Histone H3K4 Demethylase SPR-5 is reciprocally up-regulated upon lack of each other and the mutants show increased H3K4me2 levels in the germline, indicating that AMX-1 and SPR-5 regulate H3K4me2 demethylation. Loss of AMX-1 function activates the CHK-1 kinase acting downstream of ATR and leads to the accumulation of RAD-51 foci and increased DNA damage-dependent apoptosis in the germline. AMX-1 is required for the proper expression of mismatch repair component MutL/MLH-1 and sensitivity against ICLs. Interestingly, formation of ICLs lead to ubiquitination-dependent subcellular relocalization of AMX-1. Taken together, our data suggest that AMX-1 functions in ICL repair in the germline.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone methylation levels and interact with the Histone Demethylase lsd1 spr 5 in caenorhabditis elegans
Genetics, 2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone Demethylase LSD1 was originally discovered by removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1). Several studies suggest that LSD1 plays roles in meiosis as well as in the epigenetic regulation of fertility given that, in its absence, there is evidence of a progressive accumulation of H3K4me2 and increased sterility through generations. In addition to the progressive sterility phenotype observed in the mutants, growing evidence for the importance of Histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone methylation is involved in DNA damage repair, and only a few studies have focused on the roles of Histone Demethylases in germline maintenance. Here, we show that the Histone Demethylase LSD1/CeSPR-5 interacts with the Fanconi anemia (FA) protein FANCM/CeFNCM-1 using biochemical, cytological, and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S phase-checkpoint activation, and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5, suggesting coordination between this Histone Demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance, regardless of the presence of replication stress. Our study reveals a connection between FA and epigenetic maintenance and therefore provides new mechanistic insight into the regulation of Histone methylation in DNA repair.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone methylation levels and interact with the Histone Demethylase lsd1 spr 5 in c elegans
bioRxiv, 2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone Demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of Histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone methylation is involved in DNA damage repair and only a few studies have been focused on the roles of Histone Demethylases in germline maintenance. Here, we show that the Histone Demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this Histone Demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of Histone methylation in DNA repair.
Sara E Beesesims - One of the best experts on this subject based on the ideXlab platform.
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Histone Demethylase amx 1 is necessary for proper sensitivity to interstrand crosslink dna damage
PLOS Genetics, 2021Co-Authors: Xiaojuan Zhang, Monica P. Colaiácovo, Sara E Beesesims, Sisi Tian, Jingjie Chen, Nara Shin, Hyun-min KimAbstract:Histone methylation is dynamically regulated to shape the epigenome and adjust central nuclear processes including transcription, cell cycle control and DNA repair. Lysine-specific Histone Demethylase 2 (LSD2) has been implicated in multiple types of human cancers. However, its functions remain poorly understood. This study investigated the Histone Demethylase LSD2 homolog AMX-1 in C. elegans and uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair. AMX-1 is a Histone Demethylase and mainly localizes to embryonic cells, the mitotic gut and sheath cells. Lack of AMX-1 expression resulted in embryonic lethality, a decreased brood size and disorganized premeiotic tip germline nuclei. Expression of AMX-1 and of the Histone H3K4 Demethylase SPR-5 is reciprocally up-regulated upon lack of each other and the mutants show increased H3K4me2 levels in the germline, indicating that AMX-1 and SPR-5 regulate H3K4me2 demethylation. Loss of AMX-1 function activates the CHK-1 kinase acting downstream of ATR and leads to the accumulation of RAD-51 foci and increased DNA damage-dependent apoptosis in the germline. AMX-1 is required for the proper expression of mismatch repair component MutL/MLH-1 and sensitivity against ICLs. Interestingly, formation of ICLs lead to ubiquitination-dependent subcellular relocalization of AMX-1. Taken together, our data suggest that AMX-1 functions in ICL repair in the germline.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone methylation levels and interact with the Histone Demethylase lsd1 spr 5 in caenorhabditis elegans
Genetics, 2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone Demethylase LSD1 was originally discovered by removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1). Several studies suggest that LSD1 plays roles in meiosis as well as in the epigenetic regulation of fertility given that, in its absence, there is evidence of a progressive accumulation of H3K4me2 and increased sterility through generations. In addition to the progressive sterility phenotype observed in the mutants, growing evidence for the importance of Histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone methylation is involved in DNA damage repair, and only a few studies have focused on the roles of Histone Demethylases in germline maintenance. Here, we show that the Histone Demethylase LSD1/CeSPR-5 interacts with the Fanconi anemia (FA) protein FANCM/CeFNCM-1 using biochemical, cytological, and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S phase-checkpoint activation, and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5, suggesting coordination between this Histone Demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance, regardless of the presence of replication stress. Our study reveals a connection between FA and epigenetic maintenance and therefore provides new mechanistic insight into the regulation of Histone methylation in DNA repair.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone methylation levels and interact with the Histone Demethylase lsd1 spr 5 in c elegans
bioRxiv, 2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone Demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of Histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone methylation is involved in DNA damage repair and only a few studies have been focused on the roles of Histone Demethylases in germline maintenance. Here, we show that the Histone Demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this Histone Demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of Histone methylation in DNA repair.
Andrea Mattevi - One of the best experts on this subject based on the ideXlab platform.
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new roles of flavoproteins in molecular cell biology Histone Demethylase lsd1 and chromatin
FEBS Journal, 2009Co-Authors: Federico Forneris, Elena Battaglioli, Andrea Mattevi, Claudia BindaAbstract:Lysine-specific Demethylase 1 (LSD1) is an enzyme that removes methyl groups from mono- and dimethylated Lys4 of Histone H3, a post-translational modification associated with gene activation. Human LSD1 was the first Histone Demethylase to be discovered and this enzymatic activity is conserved among eukaryotes. LSD1 has been identified in a number of chromatin-remodeling complexes that control gene transcription and its Demethylase activity has also been linked to pathological processes including tumorigenesis. The 852-residue sequence of LSD1 comprises an amine oxidase domain which identifies a family of enzymes that catalyze the FAD-dependent oxidation of amine substrates ranging from amino acids to aromatic neurotransmitters. Among these proteins, LSD1 is peculiar in that it acts on a protein substrate in the nuclear environment of chromatin-remodeling complexes. This functional divergence occurred during evolution from the eubacteria to eukaryotes by acquisition of additional domains such as the SWIRM domain. The N-terminal part of LSD1, predicted to be disordered, contains linear motifs that might represent functional sites responsible for the association of this enzyme with a variety of transcriptional protein complexes. LSD1 shares structural features with other flavin amine oxidases, including the overall fold of the amine oxidase domain region and details in the active site that are relevant for amine substrate oxidation.
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a novel mammalian flavin dependent Histone Demethylase
Journal of Biological Chemistry, 2009Co-Authors: Aristotele Karytinos, Giuseppe Ciossani, Federico Forneris, Claudia Binda, Elena Battaglioli, Antonella Profumo, Andrea MatteviAbstract:Methylation of Lys residues on Histone proteins is a well known and extensively characterized epigenetic mark. The recent discovery of lysine-specific Demethylase 1 (LSD1) demonstrated that lysine methylation can be dynamically controlled. Among the Histone Demethylases so far identified, LSD1 has the unique feature of functioning through a flavin-dependent amine oxidation reaction. Data base analysis reveals that mammalian genomes contain a gene (AOF1, for amine-oxidase flavin-containing domain 1) that is homologous to the LSD1-coding gene. Here, we demonstrate that the protein encoded by AOF1 represents a second mammalian flavin-dependent Histone Demethylase, named LSD2. The new Demethylase is strictly specific for mono- and dimethylated Lys4 of Histone H3, recognizes a long stretch of the H3 N-terminal tail, senses the presence of additional epigenetic marks on the Histone substrate, and is covalently inhibited by tranylcypromine. As opposed to LSD1, LSD2 does not form a biochemically stable complex with the C-terminal domain of the corepressor protein CoREST. Furthermore, LSD2 contains a CW-type zinc finger motif with potential zinc-binding sites that are not present in LSD1. We conclude that mammalian LSD2 represents a new flavin-dependent H3-Lys4 Demethylase that features substrate specificity properties highly similar to those of LSD1 but is very likely to be part of chromatin-remodeling complexes that are distinct from those involving LSD1.
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Human Histone Demethylase LSD1 Reads the Histone Code
The Journal of biological chemistry, 2005Co-Authors: Federico Forneris, Claudia Binda, Maria A. Vanoni, Elena Battaglioli, Andrea MatteviAbstract:Human Histone Demethylase LSD1 is a flavin-dependent amine oxidase that catalyzes the specific removal of methyl groups from mono- and dimethylated Lys4 of Histone H3. The N-terminal tail of H3 is subject to various covalent modifications, and a fundamental question in LSD1 biology is how these epigenetic marks affect the Demethylase activity. We show that LSD1 does not have a strong preference for mono- or dimethylated Lys4 of H3. Substrate recognition is not confined to the residues neighboring Lys4, but it requires a sufficiently long peptide segment consisting of the N-terminal 20 amino acids of H3. Electrostatic interactions are an important factor in protein-substrate recognition, as indicated by the high sensitivity of Km to ionic strength. We have probed LSD1 for its ability to demethylate Lys4 in presence of a second modification on the same peptide substrate. Methylation of Lys9 does not affect enzyme catalysis. Conversely, Lys9 acetylation causes an almost 6-fold increase in the Km value, whereas phosphorylation of Ser10 totally abolishes activity. LSD1 is inhibited by a demethylated peptide with an inhibition constant of 1.8 microM, suggesting that LSD1 can bind to H3 independently of Lys4 methylation. LSD1 is a chromatin-modifying enzyme, which is able to read different epigenetic marks on the Histone N-terminal tail and can serve as a docking module for the stabilization of the associated corepressor complex(es) on chromatin.
Julie Secombe - One of the best experts on this subject based on the ideXlab platform.
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the Histone Demethylase kdm5 is required for synaptic structure and function at the drosophila neuromuscular junction
Cell Reports, 2021Co-Authors: Helen M Belalcazar, Emily L Hendricks, Sumaira Zamurrad, Faith L W Liebl, Julie SecombeAbstract:Mutations in the genes encoding the lysine Demethylase 5 (KDM5) family of Histone Demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required presynaptically for neuroanatomical development and synaptic function. The Jumonji C (JmjC) domain-encoded Histone Demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles, is required for appropriate synaptic morphology and neurotransmission. The activity of the C5HC2 zinc finger is also required, as an ID-associated mutation in this motif reduces NMJ bouton number, increases bouton size, and alters microtubule dynamics. KDM5 therefore uses Demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene-regulatory programs.
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the Histone Demethylase kdm5 is required for synaptic structure and function at the drosophila neuromuscular junction
Social Science Research Network, 2020Co-Authors: Helen M Belalcazar, Emily L Hendricks, Sumaira Zamurrad, Faith L W Liebl, Julie SecombeAbstract:Mutations in the genes encoding the KDM5 family of Histone Demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded Histone Demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses Demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.