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DNA replication initiation requires precise MCM2-7 assembly. Here, the authors reveal cryo-EM structures of human MCM2-7 showing unique roles of its C-terminal extensions, defining how flexible yet accurate helicase loading ensures genome-wide replication initiation.

DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.

Using degron approaches, the authors show that cancer cells experiencing prolonged DNA methylation loss—without substantial DNA damage—undergo non-canonical senescence. This has important potential implications for cancer treatment.

DNA replication in the human genome occurs preferentially at initiation zones (IZs). Here, the authors identify TRESLIN-MTBP as a limiting factor for replication initiation whose loading onto DNA-bound MCM defines IZs. This process establishes IZs and replication timing in human cells.

It has long been thought that two enzymes, the kinases CDC7 and CDK2, are both needed to trigger DNA replication in mammalian cells. This view is challenged by evidence that offers a revised view of which kinases are essential.

Mitotic DNA synthesis (MiDAS) has been proposed to utilize break-induced DNA replication, a form of homology-directed DNA repair (HDR). Here, the authors find that core DNA end-resection factors required for HDR, including MRE11, CtIP and BRCA1, and a RecQ family helicase, WRN, are essential for MiDAS.

DNA replication stress can generate under-replicated DNA regions which is fixed by an atypical form of DNA repair synthesis in mitosis (MiDAS). Here the authors show that translesion and replicative DNA polymerases cooperate via the POLD3 subunit to complete MiDAS in human cells.

Human RIF1 protein protects cells from DNA replication stress, through mechanisms that remain uncertain. Here the authors demonstrate that the RIF1-Long isoform interacts with BRCA1 upon extended replication stress, enabling RAD51-dependent repair of broken replication forks.

Accurate chromosome segregation into daughter cells depends on proper compaction and disentanglement. The authors uncover SRBD1 as a key mediator of these essential processes that localizes topoisomerase IIα to mitotic chromosomes.

Here, the authors capture the mitotic chromosome assembly as molecular events of nucleosomes in living human cells, investigating how condensins and nucleosome-nucleosome interactions constrain chromatin during the assembly process in mitosis.

Mitotic spindle assembles in each blastomere to segregate duplicated chromosomes during cleavage of the fertilized egg. Here, the authors establish functional assays in fish embryos and find that Ran-GTP assembles a microtubule network at the metaphase spindle center that is essential for chromosome segregation.

Targeted protein degradation is a powerful tool, but difficult to achieve in vivo with high specificity and control. Here, the authors develop two in vivo targeted protein degradation systems in mice, which enable the selective degradation of target proteins in a cell type-specific manner and can be applied in both fetuses and neonates.

The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.

Profiling of human DNA polymerase Polε and Polα demonstrates their roles in leading and lagging strand DNA synthesis, and their independent measures allowed accurate predictions of replication dynamics and effects of transcription.

A study shows that the three-dimensional conformation of the human genome influences the positioning of DNA replication initiation zones, highlighting cohesin-mediated loop anchors as essential determinants of their precise location.

Auxin-inducible degron systems can be leaky and require high doses of auxin. Here the authors establish AID2 which uses an OsTIR1 mutant and the ligand 5-Ph-IAA to overcome these problems and establish AID-mediated target depletion in mice.

The TRAIP E3 ubiquitin ligase is essential for genome integrity, mutations lead to primordial dwarfism in patients. Here, the authors show that TRAIP degradation in S-phase, results in cell arrest due to DNA damage caused by replication-transcription conflicts.

High-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO) reveals more than 300 factors that influence genome folding during interphase, including 43 genes that were validated as either increasing or decreasing interactions between topologically associating domains.

The role of exosomes in intercellular communication is well established, however less in known about the biological roles of exosome secretion in exosome-secreting cells. Here the authors show that exosome secretion controls cellular homeostasis in exosome-secreting cells by removing harmful cytoplasmic DNA from cells.

A degradation pathway found in plants, dependent on the hormone auxin, can be transplanted and harnessed to induce rapid and reversible target protein degradation in both yeast and animal cells.

Proteins brought to an E3 ubiquitin ligase are polyubiquitylated for rapid degradation via the proteasome. A new study developed a tag-based degradation system using heterobifunctional degradation inducers called dTAGs, which rapidly depleted FKBP12^F36V-fused proteins in cultured cells and in mice.

Using conditional mutants of AID based on auxin-inducible degron system (AID2 cells), controlled immunoglobulin gene rearrangements in the B cell line DT40 facilitate the generation and stabilization of antigen-specific clones.

The levels of catalytic subunit of the RNaseH2 enzyme, RNAseH2A, decrease during senescence promoting nucleotide accumulation and a senescence-associated secretory phenotype.