DNA copy-number control through inhibition of replication fork progression

Proper control of DNA replication is essential to ensure faithful transmission of genetic material and prevent chromosomal aberrations that can drive cancer progression and developmental disorders. DNA replication is regulated primarily at the level of initiation and is under strict cell-cycle regulation. Importantly, DNA replication is highly influenced by developmental cues. In Drosophila, specific regions of the genome are repressed for DNA replication during differentiation by the SNF2 domain-containing protein SUUR through an unknown mechanism. We demonstrate that SUUR is recruited to active replication forks and mediates the repression of DNA replication by directly inhibiting replication fork progression instead of functioning as a replication fork barrier. Mass spectrometry identification of SUUR-associated proteins identified the replicative helicase member CDC45 as a SUUR-associated protein, supporting a role for SUUR directly at replication forks. Our results reveal that control of eukaryotic DNA copy number can occur through the inhibition of replication fork progression

Динамика клинических симптомов фиброзно-кистозной мастопатии на фоне трансдермаль-ного геля микронизированного прогестерона: результаты российского многоцентрового наблюдательного исследования БРЕСТ

Objective. To assess the dynamics offibrocystic mastopathy symptoms regression when applying monotherapy with transdermal gel of micronized progesterone continuously for 3 and 6 months under conditions of routine clinical practice. Materials and methods. The study included 1044female patients of 34.8 ± 0.2 years of age diagnosed with diffuse mastopathy with predominant glandular component and diffuse fibrocystic mastopathy with predominant cystic component. All the patients received therapy with transdermal gel of micronized progesterone (Progestogel product) for 3and 6 months. The data related to dynamics of the disease symptoms were evaluated: clinical examination of the lacteal gland was performed, ultrasound and mammography examinations were performed, with assessment according to Bi-RADS categories. Intensity of the pain sense modality was evaluated in dynamics using visual analog scale (VAS) of pain. Statistical analysis of the collected data was carried out using IBM SPSS 23 software. Results. In 3-6 months of the continuous use of Progestogel product, a significant reduction in the amount of the earlier revealed thickened tissue areas was observed during ultrasound examination, including the areas of 1-2 cm and those exceeding 2 cm (hyperplastic lobules, cysts). According to the analysis of the mammographic conclusions, in the course of the therapy the signs of the fat involution build-up were observed as reducing from 9.1% to 1.3%, the signs of focal fibrosis reduced from 12.9% to 5.3%; the proportion of the patients with diffuse fibrocystic mastopathy with predominant cystic component reduced by 22.4% (from 56.6% to 34.2%). Significant improvement of the disease course is as well demonstrated by the dynamics of the changes as per the assessment according to Bi-RADS categories (p < 0.05). The intensity of the pain in the mammary glands significantly reduced in the therapy dynamics; before treatment it was 62.22 ± 0.84 scores, in 3 months 27.33 ± 0.70 scores (p < 0.001), in 6 months 9.33 ± 0.46scores (p < 0.001). Conclusion. The data obtained show the improvement of the life quality and reduction in the pain syndrome intensity in patients with mastalgia/mastodynia.Цель исследования. Оценить динамику регрессии симптомов фиброзно-кистозной мастопатии при применении трансдермального геля микронизированного прогестерона в непрерывном режиме в течение 3 и 6месяцев.. Материал и методы. В исследовании приняли участие 1044 пациенток 34,8±0,2лет с диагнозом диффузной мастопатии с преобладанием железистого компонента и диффузной фиброзно-кистозной мастопатии с преобладанием кистозного компонента. Все пациентки получали терапию трансдермальным гелем микронизированного прогестерона (препаратом прожестожель) в течение 3-6 месяцев. Выполняли клинический осмотр молочной железы, проводили ультразвуковое и маммографическое исследование, оценку по шкале BI-RADS (Breast Imaging Reporting and Database System), оценку интенсивности болевых ощущений с использованием визуально-аналоговой шкалы боли. Статистический анализ данных выполнялся с использованием программы IBM SPSS 23. Результаты. Через 3-6месяца непрерывного применения препарата прожестожель при УЗИ отмечено достоверное уменьшение числа выявленных участков уплотненной структуры, в том числе размерами 1-2 см и более 2-х см (гиперплазированные дольки, кисты). Согласно анализу маммографических заключений в течение терапии доля жировой инволюции изменилась с 9,1% до 1,3%, очагового фиброза снижались с 12,9% до 5,3%; доля пациенток ДФКМ с преобладанием кистозного компонента сократилась на 22,4% (с 56,6% до 34,2%). Достоверное улучшение течения заболевания демонстрирует также динамика изменений по шкале BI-RADS (p<0,05). Интенсивность боли в молочной железе достоверно уменьшалась в динамике терапии: до лечения 62,22±0,84 балла - через 3 месяца 27,33±0,70 балла (p<0,001), через 6месяцев 9,33±0,46балла (p<0,001). Заключение. Полученные данные свидетельствуют о снижении выраженности болевого синдрома, об улучшении качества жизни и течения заболевания у пациенток с масталгией/мастодинией

Synthesis and physiological activity of 2,3,6-triaryl-4-oxo (hydroxy, oximino, amino) piperidine

[No abstract available

Synthesis and physiological activity of 2,3,6-triaryl-4-oxo (hydroxy, oximino, amino) piperidine

[No abstract available

Interaction between the Drosophila heterochromatin proteins SUUR and HP1

SUUR (Suppressor of Under-Replication) protein is responsible for late replication and, as a consequence, for DNA underreplication of intercalary and pericentric heterochromatin in Drosophila melanogaster polytene chromosomes. However, the mechanism by which SUUR slows down the replication process is not clear. To identify possible partners for SUUR we performed a yeast two-hybrid screen using full-length SUUR as bait. This identified HP1, the well-studied heterochromatin protein, as a strong SUUR interactor. Furthermore, we have determined that the central region of SUUR is necessary and sufficient for interaction with the C-terminal part of HP1, which contains the hinge and chromoshadow domains. In addition, recruitment of SUUR to ectopic HP1 sites on chromosomes provides evidence for their association in vivo. Indeed, we found that the distributions of SUUR and HP1 on polytene chromosomes are interdependent: both absence and overexpression of HP1 prevent SUUR from chromosomal binding, whereas SUUR overexpression causes redistribution of HP1 to numerous sites occupied by SUUR. Finally, HP1 binds to intercalary heterochromatin when histone methyltransferase activity of SU(VAR)3-9 is increased. We propose that interaction with HP1 is crucial for the association of SUUR with chromatin

Contribution of the SuUR gene to the organization of epigenetically repressed regions of Drosophila melanogaster chromosomes

A significant portion of a eukaryotic genome is silent (epigenetically repressed). In Drosophila melanogaster, this portion includes mainly regions of pericentric and intercalary heterochromatin and euchromatin regions subject to position-effect variegation. Detailed study of the organization of intercalary heterochromatin regions of Drosophila melanogaster polytene chromosomes started from the discovery of the SuUR gene (Suppressor of UnderReplication). The ability of the SuUR mutation to suppress underreplication in intercalary heterochromatin regions was used for molecular tagging of these regions. We showed that underreplicated intercalary heterochromatin regions contained silent unique genes and retained the features of late replication and transcriptionally inactive chromatin state in various cell types. Over 50% of these regions contain unique genes clustered on the base of coordinated expression. The origin of clusters and putative mechanisms of their gene expression are discussed. Data on the SuUR gene, its expression, and effect on polytene chromosome structure and replication are summarized