Cytoplasmic chromatin fragments (CCFs) are structures formed by nuclear chromatin leaked into the cytoplasm in response to cellular senescence, stress, or tumorigenesis, primarily due to genomic instability and nuclear envelope rupture. These cytoplasmic DNA fragments are recognized by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and activate the cGAS–STING pathway, which promotes activation of IRF3 and NF-κB, and induces expression of type I interferons and pro-inflammatory cytokines, thereby driving the senescence-associated secretory phenotype (SASP). CCFs are not only a hallmark of cellular senescence but also a critical signaling hub that links DNA damage to chronic inflammation via SASP factors like IL-6 and IL-8, reinforcing senescence through autocrine and paracrine loops. In cancer, CCFs play distinct roles at different stages: in early-stage tumors, they induce cell cycle arrest and enhance immune surveillance, thereby suppressing tumor initiation; whereas in advanced tumors, persistent CCFs chronically activate the cGAS–STING–NF-κB signaling axis, promoting epithelial–mesenchymal transition, angiogenesis, metastasis, and immune evasion. Notably, CCFs formation is heterogeneous and regulated by key factors such as p53, 53BP1, and Lamin B1. Therefore, targeting the CCFs–cGAS–STING pathway and its upstream regulators, including mitochondrial function, autophagy, and epigenetic modifications, offers a promising strategy to alleviate aging-related diseases and improve cancer therapy by suppressing SASP and blocking tumor progression. This review summarizes the mechanisms of CCFs biogenesis, their complex roles in aging and cancer, and emerging therapeutic approaches aimed at this axis, offering insights for both basic research and clinical translation.

Transcription–replication conflicts (TRCs) are an increasingly recognized driver of genome instability in human cells. We recently identified the CUL3 adaptor KCTD10 as a sensor of co-directional TRCs, recruiting CUL3 to ubiquitinate transcriptional machinery and clear the path for replication forks. Here, we discuss the implications of this conflict-resolution pathway for human cancer. By integrating our mechanistic findings with large-scale functional genomics datasets, we identify oncogenic conditions that potentially create TRC-rich environments and render cells selectively dependent on KCTD10. These contexts reveal new mechanistic insights and potential therapeutic opportunities across a range of human cancers.

Sister chromatid cohesion, established during DNA replication, is essential for accurate chromosome segregation. While acetylation of the cohesin subunit SMC3 by ESCO1/2 promotes the recruitment of the cohesin stabilizer Sororin, this pathway is insufficient for full Sororin function. In a recent study, Jiang et al. identify a previously uncharacterized human microprotein, RSMC, as a Sororin cofactor required for sister chromatid cohesion. The authors show that RSMC interacts with Sororin, and this interaction is enhanced during S-phase by PARP1/2-mediated poly(ADP-ribosyl)ation (PARylation) of RSMC. PARylation of RSMC, triggered by DNA replication intermediates, acts in parallel with SMC3 acetylation to ensure the timely and efficient recruitment of Sororin to chromatin. Consequently, inhibition of PARP activity reduces chromatin-bound Sororin and causes cohesion defects, which can be rescued by overexpressing wild-type RSMC or Sororin, but not by PARylation- or interaction-deficient mutants. Furthermore, RSMC stimulates the anti-Wapl activity of Sororin in vitro, promoting stable cohesin binding. Taken together, the work of Jiang et al. describes a dual, replication-coupled regulatory mechanism wherein S-phase PARylation of the microprotein RSMC cooperates with SMC3 acetylation to fully enable Sororin’s function in establishing sister chromatid cohesion. This mechanism is important for maintaining genomic stability, and its dysregulation may contribute to chromosome segregation errors observed in cancer.

The 16^th International Symposium on DNA Damage Response & Human Disease (isDDRHD-2025) was held in Qingdao, China (October 17-20, 2025). The meeting assembled approximately 250 participants and featured 39 invited speakers from many countries. Scientific sessions covered the topics of mechanistic understanding and conceptual advances in the areas of the DNA damage response (DDR), genome stability, replication stress and chromatin organization, structural elucidation of repair machineries, as well as RNA-related genome maintenance. Presentations also addressed how dysregulation of DDR pathways drives human pathologies, including cancer, neuropathies and gonad development, and discussed how to target DDR pathways for therapeutic development. In addition to oral presentations, poster sessions and discussions at café-breaks and off-sessions provided further information exchanges in a relaxed and friendly atmosphere, which promoted interactions between early-career and established scientists.

Modification with UFM1 (UFMylation) has recently emerged as a versatile signaling system regulating diverse cellular processes, from endoplasmic reticulum homeostasis to genome stability. Recent studies have expanded this landscape by revealing a direct role of UFMylation in the core machinery of DNA replication. Specifically, UFMylation of MCM5 is required for optimal activation of the CDC45–MCM–GINS (CMG) helicase, the molecular engine that governs origin firing and drives replication fork progression. This discovery introduces a previously unrecognized regulatory layer into the DNA replication program and positions UFMylation as an important coordinator of genome duplication, whose disruption provides a mechanistic explanation for developmental disorders such as microcephalic primordial dwarfism (MPD), while more subtle or progressive dysregulation may have important implications for genome stability across ageing and cancer.