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Common fragile sites (CFSs) are chromosomal regions that are prone to form breaks or gaps during mitosis, in particular following replication stress. The mechanisms modulating CFS expression and promoting safe chromatid transmission to daughter cells are not clear. Now CFS expression is shown to reflect the activity of the MUS81–EME1 resolvase complex which cooperates with the dissolving action of the BLM helicase to prevent uncontrolled chromosome breakage and to promote genome integrity.
Fetal haematopoietic stem cells (HSCs) self-renew extensively to build the blood system from scratch. The protein Lin28b negatively regulates the microRNA let-7 to keep levels of its target Hmga2 high, hence conferring high self-renewal potential to fetal HSCs. This regulatory circuit can be experimentally modulated to boost the lower self-renewal activity of quiescent adult HSCs.
Senescence, a cell-autonomous tumour suppressor mechanism, also has pro-tumorigenic effects on neighbouring pre-malignant cells through the senescence-associated secretory phenotype (SASP). The SASP is now shown to be regulated by inflammasomes and to induce paracrine senescence in healthy cells, indicating that senescence may also represent a non-cell-autonomous tumour suppressor mechanism linked to innate immunity.
Multiple activities cooperate to determine the architecture of the mitotic spindle. Kip3 is a kinesin-8 motor protein in budding yeast that acts as a microtubule depolymerase. Now Kip3 is shown to also crosslink and slide antiparallel microtubules, providing additional insights into how kinesin-8 motors control spindle integrity.
The transcription factor p73, a close relative of p53, has complex yet poorly understood roles in tumorigenesis. TAp73, a p73 variant, has now been shown to promote cancer cell proliferation by regulating glucose metabolism to control cellular biosynthetic pathways and antioxidant capacity.
Deficiency in dystrophin leads to death with cardiorespiratory failure in humans, but mice lacking dystrophin have minimal heart defects. Blau and colleagues find that mice that lack dystrophin and have shorter telomeres exhibit cardiac defects similar to human patients, with an increase in oxidative stress. The authors also found that onset of cardiac defects could be delayed by antioxidant treatments and that, strikingly, patients also have shortened telomeres.
Surani and colleagues use single-cell transcriptomics analysis in a model of mouse primordial germ cell specification to analyse the collaboration between three transcription factors, BLIMP1, PRDM14 and AP2γ, in determining germ cell fate. They find that BLIMP1 binds directly to repress somatic and cell proliferation genes, and at the same time induces AP2γ, which acts together with PRDM14. The three factors are sufficient for specification and form a tripartite interdependent transcriptional network.
Fetal haematopoietic stem cells (HSCs) display higher self-renewal potential than their adult counterparts. Eaves and colleagues show that adult HSCs express lower levels of Lin28b and higher levels of let-7 miRNA. They demonstrate that Lin28 overexpression, as well as that of Hmga2 (a target of let-7), induces fetal properties in adult HSCs. Conversely, HMGA2 loss in fetal HSCs results in premature induction of adult HSC self-renewal properties.
Martin and colleagues analyse the mechanism underlying Twist- and Rho1-driven apical constriction of ventral furrow cells in Drosophila. They characterize the spatial localization of the Rho1 effectors Rok1 and Dia, and their effects on the actomyosin network and adherens junctions.
In mouse oocytes, Rab11a-positive vesicles are associated with actin nucleators. Schuh and colleagues find that these vesicles function as storage reservoirs for actin nucleators, that the actin network can be modulated by altering the number of Rab11a vesicles, and that actin dynamics affect the positioning of the meiotic spindle.
Pellman and colleagues report that the Kip3 kinesin-8 has antiparallel microtubule-sliding activity. The ability of Kip3 to slide antiparallel microtubules, along with its known role in destabilizing microtubules, are important for regulating spindle length.
Verlhac, Terret and colleagues report that softening of the mouse oocyte cortex during meiosis I is needed for spindle migration and positioning. They show that Mos/mAPK signalling triggers myosin II exclusion from the cortex and an Arp2/3-dependent cortical F-actin thickening that contributes to cortical softening.
The ATM checkpoint kinase and the tumour suppressor ARF are thought to act separately to counteract tumorigenesis. Bartek, Gorgoulis and colleagues find that in transformed cells, ATM negatively regulates the levels and activity of ARF. In cell culture and mouse xenograft experiments, ATM inhibition promotes ARF-mediated tumour suppression, demonstrating an interplay between these pathways.
A property of oncogene-induced senescence (OIS) is the induction of a secretory phenotype, termed the senescence-associated secretome (SASP). Gil and colleagues now provide evidence that senescence can be transmitted in a paracrine manner, by showing that induction of the SASP in cells undergoing OIS by inflammasome-mediated interleukin-1 signalling can promote senescence of normal neighbouring cells.
The p53 homologue TAp73 is frequently overexpressed in tumours, suggesting it provides an advantage to cancer cells. Yang and colleagues have investigated the role of TAp73 in tumour cell proliferation and showed that TAp73, but not p53, is a transcriptional activator of glucose-6-phosphate dehydrogenase. Increased expression of this gene promotes the pentose phosphate pathway flux, leading to enhanced biosynthesis and antioxidant defence, both of which have been shown to support optimal cell proliferation and tumour formation.
Chromosomal fragile sites (CFSs) are prone to breakage and thus can cause genomic instability. Hickson and colleagues demonstrate that the MUS81 endonuclease localizes to CFSs and mediates their processing, revealing that CFS cleavage is an active process.
Breakage and rearrangement of common fragile sites (CFSs) can cause genomic instability. Rosselli and colleagues demonstrate that the endonuclease subunit ERCC1 and the endonuclease MUS18–EME1 are recruited to FANCD2-binding CFSs in mitosis to mediate their processing.
