Structural mechanism for the selective phosphorylation of DNA-loaded MCM double hexamers by the Dbf4-dependent kinase

Loading of the eukaryotic replicative helicase onto replication origins involves two MCM hexamers forming a double hexamer (DH) around duplex DNA. During S phase, helicase activation requires MCM phosphorylation by Dbf4-dependent kinase (DDK), comprising Cdc7 and Dbf4. DDK selectively phosphorylates loaded DHs, but how such fidelity is achieved is unknown. Here, we determine the cryogenic electron microscopy structure of Saccharomyces cerevisiae DDK in the act of phosphorylating a DH. DDK docks onto one MCM ring and phosphorylates the opposed ring. Truncation of the Dbf4 docking domain abrogates DH phosphorylation, yet Cdc7 kinase activity is unaffected. Late origin firing is blocked in response to DNA damage via Dbf4 phosphorylation by the Rad53 checkpoint kinase. DDK phosphorylation by Rad53 impairs DH phosphorylation by blockage of DDK binding to DHs, and also interferes with the Cdc7 active site. Our results explain the structural basis and regulation of the selective phosphorylation of DNA-loaded MCM DHs, which supports bidirectional replication.

The Liturgical Singing Tradition of the Old Believers Priests of the Village of Koida (Based on the Materials of the Pushkin House Expedition in 1975 and 1976)

В 1975 и 1976 годах состоялись фольклорные экспедиции Института русской литературы в с.Койда Мезенского р-на Архангельской области, в ходе которых были записаны разнообразные в стилевом и историческом отношении духовные стихи, а также богослужебные песнопения. До настоящего времени коллекция звукозаписей, хранящаяся в Фонограммархиве ИРЛИ, не становилась предметом специального изучения. В ходе исследования удалось атрибутировать гимнографические тексты, выделить особенности распевов и духовных стихов, выявить их источники, частично реконструировать условия звукозаписи. На основе материалов более поздних фольклорно-археографических экспедиций ИРЛИ были восстановлены сведения о жизни старообрядческой общины, которая принадлежала к белокриницкому согласию. Коллекция богослужебных песнопений в музыкальном отношении разнообразна: она содержит пение «по напевке», «на глас», распевы письменной традиции, памятогласие. Внебогослужебная лирика представлена популярными духовными стихами позднего происхождения, за исключением эсхатологических стихов, распевы которых опираются на богослужебную традицию гласового пения. In 1975 and 1976, the Institute of Russian Literature (the Pushkin House) arranged expeditions to the village of Koida, Mezensky District, Arkhangelsk Region, during which spiritual verses and liturgical chants diverse in style and history were recorded. Until now, the collection of sound recordings (32 items) stored in the Phonogram Archive has not been a subject of special study. In the course of the research, it has become possible to attribute hymnographic texts, to highlight specifics of the chants and spiritual verses, to identify their sources, and partially reconstruct conditions of the sound recording. The materials of later folklore and archaeographic expeditions, provided the following information: facts about the life of the Old Believer’s community that belonged to the Belokrinitsky concord, the names of mentors, forms of mentoring and transmitting the singing tradition. The chants and spiritual verses were recorded from two significant performers — mentors Nadezhda Malygina and Nikandr Malygin. The collection of chants is diverse and contains oral and written versions of chants, mnemonic (pamyatoglasie). Non-liturgical music is represented by popular spiritual poetry of late origin, except for eschatological verses, the melody of which is similar to the chant.

Human ORC/MCM density is low in active genes and correlates with replication time but does not delimit initiation zones

Eukaryotic DNA replication initiates during S phase from origins that have been licensed in the preceding G1 phase. Here, we compare ChIP-seq profiles of the licensing factors Orc2, Orc3, Mcm3, and Mcm7 with gene expression, replication timing and fork directionality profiles obtained by RNA-seq, Repli-seq and OK-seq. ORC and MCM are significantly and homogeneously depleted from transcribed genes, enriched at gene promoters, and more abundant in early- than in late-replicating domains. Surprisingly, after controlling these variables, no difference in ORC/MCM density is detected between initiation zones, termination zones, unidirectionally replicating and randomly replicating regions. Therefore, ORC/MCM density correlates with replication timing but does not solely regulate the probability of replication initiation. Interestingly, H4K20me3, a histone modification proposed to facilitate late origin licensing, was enriched in late replicating initiation zones and gene deserts of stochastic replication fork direction. We discuss potential mechanisms specifying when and where replication initiates in human cells.

Joel

This essay offers an introduction to the major literary and theological issues of the book of Joel. It shows how an agrarian disaster (locusts and drought) is transformed into a prophecy concerning the nations. The book’s engagement with with earlier texts ( especially those relating to the “Day of Yahweh”) attests to its late origin, and its ending reflects late theological thinking about the relationship between Israel and the nations, portraying Yahweh as the ruler of the whole world. In its final form, the book is shaped by a vague specificity that allows its use and application over a broad period of time.

The Acrostic Version of the Slavonic Translation of Two George Skylitzes’ Canons for St. John of Rila

The modern liturgical “Green Menaia”, published by the Moscow Patriarchate in 1978–1989 and reprinted with additions in 2002, as part of the Service of St. John of Rilа (August 18) includes a Slavonic translation of the complete Octoechos cycle of canons for this Bulgarian saint, composed in Greek by George Skylitzes in the second half of the 12th century (the canon of the 1st tone is included in the service, and the rest are given in the appendix to it). In addition, the same canon of the 8th tone, but without the rest of the canons of the cycle, is contained in the service to the Transfer of the relics of St. John of Rila (October 19) of the same Menaia. The Greek original of this cycle remains unknown, and its medieval Slavonic translation (originated in Bulgaria) is known from merely two complete manuscript copies of the Rila Monastery, although individual canons are read in more manuscripts. The scholarly edition of the cycle was produced by L. Nenova in 2012, therefore the “Green Menaia” should be considered their first (although not scholarly, a liturgical) publication. Here, the text of the Slavonic translation is edited, and in the first and last canons arbitrary Slavonic acrostics are additionally inscribed, which have nothing to do with the textual history of these canons: ДИВЕН БОГ ВО СВЯТИХ СВОИХ БОГ ИСРАИЛЕВ (the canon of the 1st tone); РАДУИСЯ ИОАННЕ СВЕТИЛНИЧЕ ПРЕСВЕТЛИИ (the canon of the 8th tone). The acrostics were composed by rearranging words and making short additions at the beginning of the troparia, therefore this version should be considered a separate (acrostic) edition of the Slavonic translation of George Skylitzes’ canons for St. John of Rila. At least one of the two Rila manuscripts must have served as a basis for this version, created specifically for the “Green Menaia”. Despite its late origin, it clearly demonstrates the possibility of a secondary introduction of a Slavic acrostic into the Slavonic translation of a Byzantine canon, which is to be considered when studying the earliest Slavic hymnography.

Human ORC/MCM density is low in active genes and correlates with replication time but does not solely define replication initiation zones

Eukaryotic DNA replication initiates during S phase from origins that have been licensed in the preceding G1 phase. Here, we compare ChIP-seq profiles of the licensing factors Orc2, Orc3, Mcm3, and Mcm7 with gene expression, replication timing and fork directionality profiles obtained by RNA-seq, Repli-seq and OK-seq. ORC and MCM are strongly and homogeneously depleted from transcribed genes, enriched at gene promoters, and more abundant in early-than in late-replicating domains. Surprisingly, after controlling these variables, no difference in ORC/MCM density is detected between initiation zones, termination zones, unidirectionally replicating and randomly replicating regions. Therefore, ORC/MCM density correlates with replication timing but does not solely regulate the probability of replication initiation. Interestingly, H4K20me3, a histone modification proposed to facilitate late origin licensing, was enriched in late replicating initiation zones and gene deserts of stochastic replication fork direction. We discuss potential mechanisms that specify when and where replication initiates in human cells.

Origin of Words Denoting ‘Salt’ in the Selkup and Ugric Languages

In the Finno-Permian languages, the words denoting ‘salt’ are loans (from an Indo-European language of the Proto-Baltic or Iranian groups), while in the North Samoyedic languages, they are later innovations (a word meaning ‘white’). Their appearance can be associated with the spread of cattle breeding and agriculture among the respective peoples. The situation is similar in the Ugric languages and in Selkup, but the sources of words for ‘salt’ are different there. The Khanty (*sФl-nк) and Northern Mansi (solwкl) words for ‘salt’ were borrowed from the Permian *sЫl ‘salt’, or, more precisely, from its derivatives (compare Udmurt s2lal), between the first half and mid-first millennium AD, which mainly reflects the hunting and fishing lifestyle of the Ob-Ugrians before and during the contact (the word was borrowed to denote salt as a preservative from the Permians who were familiar with agriculture and cattle breeding). In the Mansi dialects except for the Northern dialect and in the Selkup language (in most dialects), apparently, the older word for ‘salt’ was kept (Mans. *CЁkkг ~ Selk. *њяq < *ќяq) going back to the Proto-Ugric times (there is a Hungarian parallel: szik ‘swamp; salt marsh, ground soda outlets’) when the Ugrians were familiar with the producing economy. Its only possible source may be the Yeniseian *VкЭ ‘salt’, which is of a Sino-Caucasian origin, or a word of some Sino-Caucasian language, since one can assume that this term has also penetrated into the languages of the peoples of the Far East. The Hungarian word for ‘salt’ (sв < *VaU) has a relatively late origin and is most likely to have been borrowed by the ancient Hungarians from the Adyghe languages (*ќкʁwк) before the Hungarian land-taking (between the fifth and ninth centuries).

Island-arc augite-bytownite-labradoritic dacites of the Kara-Dag, Crimea

Island-arc calc-alcaline dacites (66,7% of SiO2, 3,4% of Na2O, 1,9% of K2O) compose a subvolcanic body among tuffs, andesites and trachyandesites in the east of the Kara-Dag volcanic massif of the Rocky Crimea. The unique features of dacites is abundance of plagioclase phenocrysts (the central zone is bytownite Ca75–72Na24–27K0,5–1; the intermediate and external zones is labradorite Ca67–52Na32–47K1) and low-Ti augite (augite Ca43–41Mg41–38Fe16–21 with 1–2% of Al2O3 composes the core; the intermediate and external zones is augite Ca43–41Mg41–38Fe16–21 with 1–2% Al2O3). Titanomagnetite, ilmenite and apatite form intergrowths with augite. Lowmagnesian titanomagnetite is enriched with manganese (up to 4,5 wt.% MnO) and zinc (up to 1,6% of ZnO); it contains from 39 to 28% of ulvospinel minal. Ilmenite, poor in Mn, contains from 10 to 25 mol.% of hematite minal that demonstrates the crystallization with the raised fO2, in other words, the water saturation of fusion. Apatite is poor in Sr, Ce and S. The trend with standard accumulation of fluorine from chlorine-hydroxyl-fluorapatite up to fluorapatite is shown. Plagioclase microlites — labradorite Ca52–50Na46–48K2–3 composes the cementing mass of rhyolitic composition (77,3% SiO2, 3,3% Na2O, 2,5% K2O) with quartz, small amounts of andesine Ca49–46Na49–52K2–3, oligoclase Ca27Na68K5 and anorthoclase in interstitions. The speciality of the described dacites is plagioclase wealth in anorthite component, what is typical for island-arc volcanites. The crystallization temperature of augite is ~1050–950 ᵒC. The crystallization temperature of associated titanomagnetite and ilmenite of early origin is ~900 ᵒC, fO2 exceed by 1 logarithmic unit the QFM buffer, their late origin crystallization temperature is ~880 ᵒC, fO2 exceed by 2 logarithmic units the QFM buffer.

Concerted activities of Mcm4, Sld3 and Dbf4 in control of origin activation and DNA replication fork progression

Eukaryotic chromosomes initiate DNA synthesis from multiple replication origins in a temporally specific manner during S phase. The replicative helicase Mcm2-7 functions in both initiation and fork progression and thus is an important target of regulation. Mcm4, a helicase subunit, possesses an unstructured regulatory domain that mediates control from multiple kinase signaling pathways, including the Dbf4-dependent Cdc7 kinase (DDK). Following replication stress in S phase, Dbf4 and Sld3, an initiation factor and essential target of Cyclin-Dependent Kinase (CDK), are targets of the checkpoint kinase Rad53 for inhibition of initiation from origins that have yet to be activated, so-called late origins. Here, whole genome DNA replication profile analysis is employed to access under various conditions the effect of mutations that alter the Mcm4 helicase regulatory domain and the Rad53 targets, Sld3 and Dbf4. Late origin firing occurs under genotoxic stress when the controls on Mcm4, Sld3 and Dbf4 are simultaneously eliminated. The regulatory domain of Mcm4 plays an important role in the timing of late origin firing, both in an unperturbed S phase and dNTP limitation. Furthermore, checkpoint control of Sld3 impacts fork progression under replication stress. This effect is parallel to the role of the Mcm4 regulatory domain in monitoring fork progression. Hypomorph mutations in sld3 are suppressed by a mcm4 regulatory domain mutation. Thus, in response cellular conditions, the functions executed by Sld3, Dbf4 and the regulatory domain of Mcm4 intersect to control origin firing and replication fork progression, thereby ensuring genome stability.