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Functional duplication of Rap1 in methylotrophic yeasts.

ABSTRACT: The telomere regulator and transcription factor Rap1 is the only telomere protein conserved in yeasts and mammals. Its functional repertoire in budding yeasts is a particularly interesting field for investigation, given the high evolutionary diversity of this group of unicellular organisms. In the methylotrophic thermotolerant species Hansenula polymorpha DL-1 the RAP1 gene is duplicated (HpRAP1A and HpRAP1B). Here, we report the functional characterization of the two paralogues from H. polymorpha DL-1. We uncover distinct (but overlapping) DNA binding preferences of HpRap1A and HpRap1B proteins. We show that only HpRap1B is able to recognize telomeric DNA directly and to protect it from excessive recombination, whereas HpRap1A is associated with subtelomere regions. Furthermore, we identify specific binding sites for both HpRap1A and HpRap1B within promoters of a large number of ribosomal protein genes (RPGs), implicating Rap1 in the control of the RP regulon in H. polymorpha. Our bioinformatic analysis suggests that RAP1 was duplicated early in the evolution of the "methylotrophs" clade, and the two genes evolved independently. Therefore, our characterization of Rap1 paralogues in H. polymorpha may be relevant to other "methylotrophs", yielding valuable insights into the evolution of budding yeasts.

SUBMITTER: Malyavko AN

PROVIDER: S-EPMC6510891 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Functional duplication of Rap1 in methylotrophic yeasts.

Malyavko Alexander N AN Petrova Olga A OA Zvereva Maria I MI Dontsova Olga A OA

Scientific reports 20190510 1

The telomere regulator and transcription factor Rap1 is the only telomere protein conserved in yeasts and mammals. Its functional repertoire in budding yeasts is a particularly interesting field for investigation, given the high evolutionary diversity of this group of unicellular organisms. In the methylotrophic thermotolerant species Hansenula polymorpha DL-1 the RAP1 gene is duplicated (HpRAP1A and HpRAP1B). Here, we report the functional characterization of the two paralogues from H. polymorp ...[more]

PMID: 31076582

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Project description:RAP GTPases, important regulators of cellular adhesion, are abundant signaling molecules in the platelet/megakaryocytic lineage. However, mice lacking the predominant isoform, RAP1B, display a partial platelet integrin activation defect and have a normal platelet count, suggesting the existence of a RAP1-independent pathway to integrin activation in platelets and a negligible role for RAP GTPases in megakaryocyte biology. To determine the importance of individual RAP isoforms on platelet production and on platelet activation at sites of mechanical injury or vascular leakage, we generated mice with megakaryocyte-specific deletion (mKO) of Rap1a and/or Rap1b Interestingly, Rap1a/b-mKO mice displayed a marked macrothrombocytopenia due to impaired proplatelet formation by megakaryocytes. In platelets, RAP isoforms had redundant and isoform-specific functions. Deletion of RAP1B, but not RAP1A, significantly reduced α-granule secretion and activation of the cytoskeleton regulator RAC1. Both isoforms significantly contributed to thromboxane A2 generation and the inside-out activation of platelet integrins. Combined deficiency of RAP1A and RAP1B markedly impaired platelet aggregation, spreading, and clot retraction. Consistently, thrombus formation in physiological flow conditions was abolished in Rap1a/b-mKO, but not Rap1a-mKO or Rap1b-mKO, platelets. Rap1a/b-mKO mice were strongly protected from experimental thrombosis and exhibited a severe defect in hemostasis after mechanical injury. Surprisingly, Rap1a/b-mKO platelets were indistinguishable from controls in their ability to prevent blood-lymphatic mixing during development and hemorrhage at sites of inflammation. In summary, our studies demonstrate an essential role for RAP1 signaling in platelet integrin activation and a critical role in platelet production. Although important for hemostatic/thrombotic plug formation, platelet RAP1 signaling is dispensable for vascular integrity during development and inflammation.

Project description:Distal Xq duplications refer to chromosomal disorders resulting from involvement of the long arm of the X chromosome (Xq). Clinical manifestations widely vary depending on the gender of the patient and on the gene content of the duplicated segment. Prevalence of Xq duplications remains unknown. About 40 cases of Xq28 functional disomy due to cytogenetically visible rearrangements, and about 50 cases of cryptic duplications encompassing the MECP2 gene have been reported. The most frequently reported distal duplications involve the Xq28 segment and yield a recognisable phenotype including distinctive facial features (premature closure of the fontanels or ridged metopic suture, broad face with full cheeks, epicanthal folds, large ears, small and open mouth, ear anomalies, pointed nose, abnormal palate and facial hypotonia), major axial hypotonia, severe developmental delay, severe feeding difficulties, abnormal genitalia and proneness to infections. Xq duplications may be caused either by an intrachromosomal duplication or an unbalanced X/Y or X/autosome translocation. In XY males, structural X disomy always results in functional disomy. In females, failure of X chromosome dosage compensation could result from a variety of mechanisms, including an unfavourable pattern of inactivation, a breakpoint separating an X segment from the X-inactivation centre in cis, or a small ring chromosome. The MECP2 gene in Xq28 is the most important dosage-sensitive gene responsible for the abnormal phenotype in duplications of distal Xq. Diagnosis is based on clinical features and is confirmed by CGH array techniques. Differential diagnoses include Prader-Willi syndrome and Alpha thalassaemia-mental retardation, X linked (ATR-X). The recurrence risk is significant if a structural rearrangement is present in one of the parent, the most frequent situation being that of an intrachromosomal duplication inherited from the mother. Prenatal diagnosis is performed by cytogenetic testing including FISH and/or DNA quantification methods. Management is multi-specialist and only symptomatic, with special attention to prevention of malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients.

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Functional duplication of Rap1 in methylotrophic yeasts.

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Functional duplication of Rap1 in methylotrophic yeasts.

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