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Meng-chao Yao - One of the best experts on this subject based on the ideXlab platform.
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drh1 a p68 related rna helicase gene is required for Chromosome Breakage in tetrahymena
Biology Open, 2016Co-Authors: Stephen L Mcdaniel, Meng-chao Yao, Erica Zweifel, Peter K W Harris, Eric S Cole, Douglas L ChalkerAbstract:The p68 DEAD box helicases comprise a widely conserved protein family involved in a large range of biological processes including transcription, splicing and translation. The genome of the ciliate Tetrahymena thermophile encodes two p68-like helicases, Drh1p and Lia2p. We show that DRH1 is essential for growth and completion of development. In growing cells, Drh1p is excluded from the nucleus and accumulates near cortical basal bodies. In contrast, during sexual reproduction, this protein localizes to meiotic micronuclei, initially in punctate foci in regions where centromeres and telomeres are known to reside and later in post-zygotic differentiating somatic macronuclei. Differentiation of the macronuclear genome involves extensive DNA rearrangements including fragmentation of the five pairs of germline-derived Chromosomes into 180 chromosomal sub-fragments that are stabilized by de novo telomere deletion. In addition, thousands of internal eliminated sequences (IESs) are excised from loci dispersed throughout the genome. Strains with DRH1 deleted from the germline nuclei, which do not express the protein during post-zygotic development, fail to fragment the developing macronuclear Chromosomes. IES excision still occurs in the absence of DRH1 zygotic expression; thus, Drh1p is the first protein found to be specifically required for Chromosome Breakage but not DNA elimination.
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A long stringent sequence signal for programmed Chromosome Breakage in Tetrahymena thermophila
Nucleic Acids Research, 2000Co-Authors: Qichang Fan, Meng-chao YaoAbstract:Programmed Chromosome Breakage occurs at 50–200 specific sites in the genome of Tetrahymena thermophila during somatic nuclear (macronuclear) differentiation. Previous studies have identified a 15 bp sequence, the Cbs (for Chromosome Breakage sequence), that is necessary and sufficient to specify these sites. In this study we determined the effects of mutations in the Cbs on its ability to specify the Chromosome Breakage site and promote new telomere formation in conjugating cells. Twenty-one constructs with single nucleotide substitutions covering all 15 positions of the Cbs were made and tested. Fourteen of them (covering 11 positions) abolished Breakage entirely, six (covering six positions, including the remaining four) caused partial loss of Breakage function and one showed no detectable effect. This result indicates that the Cbs has an exceptionally long and stringent sequence requirement. It offers no evidence that the Cbs contains a separate domain for promoting new telomere formation. In addition, we found that a partially functional Cbs retained in the macronucleus does not induce Chromosome Breakage during vegetative growth and that excess copies of this germline-specific sequence in the somatic nucleus have little deleterious effect on cell growth.
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New telomere formation coupled with site-specific Chromosome Breakage in Tetrahymena thermophila.
Molecular and Cellular Biology, 1996Co-Authors: Qichang Fan, Meng-chao YaoAbstract:Programmed Chromosome Breakage occurs in many ciliated protozoa and is accompanied by efficient new telomere formation. In this study, we have investigated the relationship between programmed Chromosome Breakage and telomere formation in Tetrahymena thermophila. Using specially constructed DNA clones containing the Breakage signal Cbs in transformation studies, we have determined the locations of telomere addition around the Breakage sites. They occur at variable positions, over 90% of which are within a small region (less than 30 bp) starting 4 bp from Cbs. This distribution is independent of the nucleotide sequence in the region or of the orientation of Cbs. In five of six cases determined, these sites occur at or before a T, and in the remaining case, the site occurs at or before a G. When sequences devoid of G or T are placed in this region, telomere addition still occurs within the region to maintain a similar distance relationship with Cbs. This efficient and healing process appears to be associated specifically with Cbs-directed Breakage, since it does not occur when DNA ends are generated by restriction enzyme digestion. These results suggest a strong mechanistic link between Chromosome Breakage and telomere formation.
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The controlling sequence for site-specific Chromosome Breakage in tetrahymena
Cell, 1990Co-Authors: Meng-chao Yao, Ching-ho Yao, Bob MonksAbstract:Site-specific Chromosome Breakage occurs in many ciliated protozoa during nuclear differentiation. We have determined the cis-acting sequence that controls this process in Tetrahymena thermophila. The Tetrahymena ribosomal RNA gene is bounded by two Breakage sites. Injection of this gene into developing macronuclei leads to Breakage at these sites. Deletion analysis has localized the sequences essential for Breakage to a 28 bp region that includes a 15 bp sequence (Cbs) known to be present in other Breakage sites. Insertions of Cbs allow Breakage to occur at new sites, which is accompanied by elimination of surrounding DNAs and formation of telomeric sequences, as it is at natural sites. Thus, Cbs is the necessary and sufficient sequence signal for Chromosome Breakage in Tetrahymena.
Diane Thompson - One of the best experts on this subject based on the ideXlab platform.
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VACTERL with hydrocephalus: Spontaneous Chromosome Breakage and rearrangement in a family showing apparent sex‐linked recessive inheritance
American Journal of Medical Genetics, 1993Co-Authors: Hungshu Wang, Alasdair G. W. Hunter, Brian Clifford, Margaret Mclaughlin, Diane ThompsonAbstract:The rate of spontaneous and mitomycin C induced Chromosome Breakage and sister chromatid exchange (SCE) was studied in three related cases diagnosed with VACTERL-H syndrome. There have been recent reports of sporadic patients with VACTERL-H in whom high rates of Chromosome Breakage were observed. This has led to the suggestion that some of these patients may represent the severe expression of Fanconi anemia. The pattern of inheritance in our family is highly suggestive of X-linked recessive inheritance supporting the hypothesis that VACTERL-H is, at least in some cases, a syndrome and not an association. © 1993 Wiley-Liss, Inc.
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vacterl with hydrocephalus spontaneous Chromosome Breakage and rearrangement in a family showing apparent sex linked recessive inheritance
American Journal of Medical Genetics, 1993Co-Authors: Hungshu Wang, Alasdair G. W. Hunter, Brian Clifford, Margaret Mclaughlin, Diane ThompsonAbstract:The rate of spontaneous and mitomycin C induced Chromosome Breakage and sister chromatid exchange (SCE) was studied in three related cases diagnosed with VACTERL-H syndrome. There have been recent reports of sporadic patients with VACTERL-H in whom high rates of Chromosome Breakage were observed. This has led to the suggestion that some of these patients may represent the severe expression of Fanconi anemia. The pattern of inheritance in our family is highly suggestive of X-linked recessive inheritance supporting the hypothesis that VACTERL-H is, at least in some cases, a syndrome and not an association. © 1993 Wiley-Liss, Inc.
Ivan K. Chinn - One of the best experts on this subject based on the ideXlab platform.
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destabilized smc5 6 complex leads to Chromosome Breakage syndrome with severe lung disease
Journal of Clinical Investigation, 2016Co-Authors: Saskia N. Van Der Crabben, Marije P. Hennus, Grant A. Mcgregor, Deborah I. Ritter, Sandesh C.s. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. ChinnAbstract:The structural maintenance of Chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in Chromosome maintenance are linked to rare Chromosome Breakage disorders. Here, we have identified a Chromosome Breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and Chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed Chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive Chromosome Breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.
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Destabilized SMC5/6 complex leads to Chromosome Breakage syndrome with severe lung disease
Journal of Clinical Investigation, 2016Co-Authors: Saskia N. Van Der Crabben, Marije P. Hennus, Grant A. Mcgregor, Deborah I. Ritter, Sandesh C.s. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. Chinn, Aaron Alt, Lucie VondrováAbstract:The structural maintenance of Chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in Chromosome maintenance are linked to rare Chromosome Breakage disorders. Here, we have identified a Chromosome Breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and Chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed Chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive Chromosome Breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.
Joanna Groden - One of the best experts on this subject based on the ideXlab platform.
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a tri serine cluster within the topoisomerase iiα interaction domain of the blm helicase is required for regulating Chromosome Breakage in human cells
Human Molecular Genetics, 2018Co-Authors: Julia Harris Behnfeldt, Jeremy Keirsey, Samir Acharya, Larissa Tangeman, April Renee Sandy Gocha, Joanna GrodenAbstract:The recQ-like helicase BLM interacts directly with topoisomerase IIα to regulate Chromosome Breakage in human cells. We demonstrate that a phosphosite tri-serine cluster (S577/S579/S580) within the BLM topoisomerase IIα-interaction region is required for this function. Enzymatic activities of BLM and topoisomerase IIα are reciprocally stimulated in vitro by ten-fold for topoisomerase IIα decatenation/relaxation activity and three-fold for BLM unwinding of forked DNA duplex substrates. A BLM transgene encoding alanine substitutions of the tri-serine cluster in BLM-/- transfected cells increases micronuclei, DNA double strand breaks and anaphase ultra-fine bridges (UFBs), and decreases cellular co-localization of BLM with topoisomerase IIα. In vitro, these substitutions significantly reduce the topoisomerase IIα-mediated stimulation of BLM unwinding of forked DNA duplexes. Substitution of the tri-serine cluster with aspartic acids to mimic serine phosphorylation reverses these effects in vitro and in vivo. Our findings implicate the modification of this BLM tri-serine cluster in regulating chromosomal stability.
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Chromosome Breakage Is Regulated by the Interaction of the BLM Helicase and Topoisomerase IIα
Cancer Research, 2011Co-Authors: Beatriz Russell, Saumitri Bhattacharyya, Jeremy Keirsey, April Sandy, Patrick Grierson, Erin M. Perchiniak, Juraj Kavecansky, Samir Acharya, Joanna GrodenAbstract:Cells deficient in the recQ-like helicase BLM are characterized by Chromosome changes that suggest the disruption of normal mechanisms needed to resolve recombination intermediates and to maintain Chromosome stability. Human BLM and topoisomerase IIα interact directly via amino acids 489-587 of BLM and colocalize predominantly in late G2 and M phases of the cell cycle. Deletion of this region does not affect the inherent in vitro helicase activity of BLM but inhibits the topoisomerase IIα-dependent enhancement of its activity, based on the analysis of specific DNA substrates that represent some recombination intermediates. Deletion of the interaction domain from BLM fails to correct the elevated Chromosome Breakage of transfected BLM-deficient cells. Our results demonstrate that the BLM-topoisomerase IIα interaction is important for preventing Chromosome Breakage and elucidate a DNA repair mechanism that is critical to maintain Chromosome stability in cells and to prevent tumor formation.
Marije P. Hennus - One of the best experts on this subject based on the ideXlab platform.
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destabilized smc5 6 complex leads to Chromosome Breakage syndrome with severe lung disease
Journal of Clinical Investigation, 2016Co-Authors: Saskia N. Van Der Crabben, Marije P. Hennus, Grant A. Mcgregor, Deborah I. Ritter, Sandesh C.s. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. ChinnAbstract:The structural maintenance of Chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in Chromosome maintenance are linked to rare Chromosome Breakage disorders. Here, we have identified a Chromosome Breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and Chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed Chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive Chromosome Breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.
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Destabilized SMC5/6 complex leads to Chromosome Breakage syndrome with severe lung disease
Journal of Clinical Investigation, 2016Co-Authors: Saskia N. Van Der Crabben, Marije P. Hennus, Grant A. Mcgregor, Deborah I. Ritter, Sandesh C.s. Nagamani, Owen S. Wells, Magdalena Harakalova, Ivan K. Chinn, Aaron Alt, Lucie VondrováAbstract:The structural maintenance of Chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in Chromosome maintenance are linked to rare Chromosome Breakage disorders. Here, we have identified a Chromosome Breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and Chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed Chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive Chromosome Breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.