Harman, A. | bioRxiv Science

bioRxiv2024

Nuclear actin and DNA replication stress regulate the recruitment of human telomerase to telomeres

The recruitment of telomerase to telomeres is a tightly regulated process which is stimulated by replication stress and mediated by the DNA damage response regulatory kinase ATR. Here, we demonstrate that nuclear filamentous actin is important for telomerase recruitment under endogenous and replication stress conditions in immortal human cells. Inhibition of nuclear actin polymerization decreases the presence of telomerase at telomeres. This process is regulated by both ATR and mTOR kinases, and employs other regulators of actin structure and function, such as WASP, ARP2/3 and myosin. Nuclear filamentous actin serves as a site for telomerase recruitment, which is mediated by telomere tethering on actin fibres in response to replication stress, allowing telomerase to localize to telomeres containing stalled replication forks. Overall, these data demonstrate that, in human cells which express telomerase, telomeric replication stress triggers the recruitment of telomerase to telomeres via a nuclear actin network, enabling telomere length maintenance.

cancer biology↗

bioRxiv2023

The microbiota and immune system non-genetically affect offspring phenotypes transgenerationally

Summary paragraphThe host-microbiota relationship has evolved to shape mammalian processes, including immunity, metabolism, and development1-3. Host phenotypes change in direct response to microbial exposures by the individual. Here we show that the microbiota induces phenotypic change not only in the individual but also in their succeeding generations of progeny. We found that germ-free mice exhibit a robust sebum secretion defect and transcriptional changes in various organs, persisting across multiple generations despite microbial colonization and breeding with conventional mice. Host-microbe interactions could be involved in this process, since T cell-deficient mice, which display defective sebum secretion4, also transgenerationally transmit their phenotype to progeny. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that epigenetic information in the gametes is required for phenotypic transmission. Accordingly, small non-coding RNAs that can regulate embryonic gene expression5 were strikingly and similarly altered in gametes of germ-free and T cell-deficient mice. Thus, we have uncovered a novel mechanism whereby the microbiota and immune system induce phenotypic changes in successive generations of offspring. This epigenetic form of inheritance could be advantageous for host adaptation to environmental perturbation, where phenotypic diversity can be introduced more rapidly than by genetic mutation.

microbiology↗