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In all eukaryotes, the initiation of DNA replication requires a stepwise assembly of factors onto the origins of DNA replication. This is pioneered by the Origin Recognition Complex, which recruits Cdc6. Together, they bring Cdt1, which shepherds MCM2-7 to form the OCCM complex. Sequentially, a second Cdt1-bound hexamer of MCM2-7 is recruited by ORC-Cdc6 to form an MCM double hexamer, which forms a part of the pre-RC. Although the mechanism of ORC binding to DNA varies across eukaryotes, how ORC is recruited to replication origins in human cells remains an area of intense investigation. This review discusses how the chromatin environment influences pre-RC assembly, function, and, eventually, origin activity. 

Abstract Hypoxia-induced alternative splicing (AS) regulates tumor progression and metastasis. Little is known about how such AS is controlled and whether higher-order genome and nuclear domain (ND) organizations dictate these processes. We observe that hypoxia-responsive alternatively spliced genes position near nuclear speckle (NS), the ND that enhances splicing efficiency. NS-resident MALAT1 long noncoding RNA, induced in response to hypoxia, regulates hypoxia-responsive AS. MALAT1 achieves this by organizing the SR-family of splicing factor, SRSF1, near NS and regulating the binding of SRSF1 to pre-mRNAs. Mechanistically, MALAT1 enhances the recruitment of SRSF1 to elongating RNA polymerase II (pol II) by promoting the formation of phase-separated condensates of SRSF1, which are preferentially recognized by pol II. During hypoxia, MALAT1 regulates spatially organized AS by establishing a threshold SRSF1 concentration near NSs, potentially by forming condensates, critical for pol II-mediated recruitment of SRSF1 to pre-mRNAs. 

Out of the several hundred copies ofrRNAgenes arranged in the nucleolar organizing regions (NOR) of the five human acrocentric chromosomes, ~50% remain transcriptionally inactive. NOR-associated sequences and epigenetic modifications contribute to the differential expression of rRNAs. However, the mechanism(s) controlling the dosage of active versus inactiverRNAgenes within each NOR in mammals is yet to be determined. We have discovered a family of ncRNAs, SNULs (Single NUcleolus Localized RNA), which form constrained sub-nucleolar territories on individual NORs and influence rRNA expression. Individual members of the SNULs monoallelically associate with specific NOR-containing chromosomes. SNULs share sequence similarity to pre-rRNA and localize in the sub-nucleolar compartment with pre-rRNA. Finally, SNULs control rRNA expression by influencing pre-rRNA sorting to the DFC compartment and pre-rRNA processing. Our study discovered a novel class of ncRNAs influencing rRNA expression by forming constrained nucleolar territories on individual NORs. 

Abstract Three recent publications on BEND3 firmly establish its role as a novel sequence‐specific transcription factor that is essential for PRC2 recruitment and maintenance of pluripotency. Here, we briefly review our current understanding of the BEND3‐PRC2 axis in the regulation of pluripotency and also explore the possibility of a similar connection in cancer. 

Abstract Error‐free genome duplication and accurate cell division are critical for cell survival. In all three domains of life, bacteria, archaea, and eukaryotes, initiator proteins bind replication origins in an ATP‐dependent manner, play critical roles in replisome assembly, and coordinate cell‐cycle regulation. We discuss how the eukaryotic initiator, Origin recognition complex (ORC), coordinates different events during the cell cycle. We propose that ORC is the maestro driving the orchestra to coordinately perform the musical pieces of replication, chromatin organization, and repair.