News & Views

Understanding how cancers react to poly(ADP-ribose) polymerase (PARP) trapping on DNA is crucial to thwart PARP inhibitor resistance. A recent study finds that trapped PARP1 is removed via the ubiquitin-dependent segregase p97, and that perturbing this molecular cascade increases PARP inhibitor cytotoxicity.

Cell fate determination by H3.3 deposition in haematopoietic stem and progenitor cells is largely unexplored. Two studies jointly support the idea that H3.3 maintains haematopoiesis balance and prevents endogenous retroviral element (ERV) activation through chromatin marks and transcriptome alterations.

Extracellular vesicles and particles have important roles in physiology and disease. Advances in isolation and characterization technologies have enabled the identification of new particles. Supermeres are the newest addition to the rapidly expanding repertoire of the cell secretome, and provide exciting opportunities for clinical translation.

Rhythmic removal of circadian clock proteins is important for the strength and periodicity of the circadian rhythm. A study now reveals that chaperone-mediated autophagy regulates the degradation of circadian proteins, and is also transcriptionally regulated by the circadian machinery. This feedback loop helps to maintain circadian oscillations.

Mitochondrial-derived vesicles (MDVs) transfer mitochondrial content to lysosomes and peroxisomes. A study now reveals that MDVs deliver β-barrel proteins and fully assembled mitochondrial complexes for lysosomal degradation, establishing an important role for MDVs in mitochondrial protein quality control.

Formerly regarded as ‘junk’ DNA, transposable elements are now thought to be players in genome evolution. A new study reveals remarkable conservation of a retrotransposon insertion acting as an alternative promoter to drive the expression of a cell cycle regulator isoform in early embryos, potentially controlling the timing of pre-implantation development.

How lymphatic vessels arise from veins is still poorly understood. A study reports the discovery of a ribosome biogenesis regulator Ddx21 as a previously unappreciated specific factor that is important for the first steps of lymphatic but not blood vessel development. The finding may lead to better strategies to selectively target lymphangiogenesis.

During the repair of DNA breaks by homologous recombination, damaged DNA seeks out intact, similar in sequence segments to use as a template. In this issue, Piazza, Bordelet and colleagues describe three-dimensional chromosome architecture remodelling during homologous recombination and show that cohesin restricts homology search in cis, independently of sister chromatid cohesion.

FGFR-altered triple negative breast cancer (TNBC) develops adaptive resistance to FGFR inhibitor therapy. A new study shows that sustained FGFR inhibition causes SWI/SNF complex eviction at YAP-recruited enhancers followed by increased mTORC1 activity. Dual inhibition of YAP or mTORC1 and FGFR has a synergistic effect on tumour growth.

The WAVE regulatory complex is well known as an orchestrator of actin dynamics at the leading edge of migrating cells. A recent study shows how mechanical effects can regulate the WAVE complex and explains the importance of forces generated by actin filaments to control new actin generation at the leading edge.

The underlying molecular and cellular mechanisms for asthma remain incompletely understood. A new study now shows that eosinophils release DNA traps that stimulate pulmonary neuroendocrine cell-mediated amplification of the allergic asthma response.

Clathrin- and dynamin-independent endocytosis is considered a major ‘default’ uptake route for cells, but a recent study describes the selective recruitment of integrin-adhesion receptor cargoes via the endocytic adaptor Swip1, which promotes breast cancer invasion and metastasis.

Cells respond to stimuli by reorganizing their contents into subcellular structures. New research demonstrates that yeast pyruvate kinase Cdc19 interacts with fructose-1,6-bisphosphate to coordinate disassembly of stress granules. These findings reveal how proteins can directly sense the cellular energy state to facilitate adaptive reorganization.

The collapse of DNA replication forks leads to the formation of single-ended DNA double-strand breaks. One would have assumed that these breaks would be repaired as soon as possible. However, a recent study suggests that a delay in DNA polymerase θ-mediated end joining until mitosis, orchestrated by BRCA2 and RAD52, favors genomic stability.

Enhancer of zeste homolog 2 (EZH2) has been shown to promote development of castration-resistant prostate cancer (CRPC) through various mechanisms. A new study now shows that a phosphorylated EZH2 interacts with the androgen receptor (AR) and reprograms AR transcriptional activity to facilitate transition of CRPC into a lineage infidelity state.

Mice deficient in the piRNA pathway display sterility only in males. Taking advantage of a more representative piRNA pathway in golden hamsters, three studies now demonstrate that the piRNA pathway is essential for fertility in hamsters of both sexes and thus strongly link this small RNA pathway to fertility regulation in both men and women.

Stem cells are the functional units of tissue repair but do not act alone. Studies on flatworms now reveal specialized populations of differentiated cells that transiently emerge to coordinate whole-body regeneration. The stem-cell-centric view of repair processes must be revised to account for the importance of cell fate dynamics beyond the niche.

Tissue-resident stem cells are capable of remarkable plasticity in areas of tissue damage, where inflammatory cells accumulate as part of the reparative response. A study in the lung now provides critical insight on how inflammatory signals alter cell-to-cell Notch signalling within the airway niche to drive stem cell plasticity.

With advanced high-throughput technologies, scientists can now use transcriptional signatures to study melanocytes as they become cancer. A new study identifies transcriptional programs at single-cell resolution across platforms and species, which enables prediction of melanoma prognosis and response to immune-checkpoint inhibitor therapy.

Lineage-specific gene expression programs in multicellular organisms are controlled by balanced ON and OFF signals, amongst which heterochromatin regulates expression by restricting activation cues. A study now provides insights into mammalian heterochromatin organisation, function and interplay with lineage-specific transcription factors.