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Genitourinary syndrome of menopause (GSM) is a chronic condition affecting a large number of women, with a major impact on their urogenital health and sexual function. It occurs at midlife because estrogen levels decline with menopause enhancing aging-related changes of the functional anatomy of the urogenital system. Unfortunately, GSM may occur early in the lifespan of women or be exacerbated following anticancer treatments, such as chemotherapy, ionizing radiation, or surgical removal of reproductive organs. Symptoms of GSM are often under-reported by women, under-estimated and under-diagnosed by health care providers (HCPs), and subsequently under-treated, despite their profound negative impact on the quality of life. The mainstay of vaginal treatments is local estrogen therapy (LET) ensuring an effective management of moderate to severe symptomatic GSM. However, LET is generally contraindicated in women with a history of hormone receptor positive cancer, due to the fear of increased recurrence or possible interference with endocrine adjuvant therapies. Among non-hormonal treatments, hyaluronic acid-based moisturizers have shown promising clinical results both in healthy women and in cancer patients or survivors. Its strong water-binding properties provide lubricating and moisturizing effects, which contribute to maintaining a proper level of hydration and viscoelasticity in several body parts, including the urinary tract and genital tissues. Hyaluronic acid-based moisturizers are effective, safe, and well tolerated; therefore, they may represent a valid option for the early management of GSM-associated symptoms in every woman with a history of cancer who is unable or unwilling to undergo hormone-based therapies. Hence, the aim of this review was to provide an overview of GSM etiology and treatment in women with natural or iatrogenic menopause, with a focus on the use of hyaluronic acid as a prophylactic treatment in the context of an integrated management proto

In the last decade, endocrine therapy strategies in perimenopausal women with hormone-responsive early breast cancer (BC) have changed and now ovarian function suppression (OFS) is recommended for the majority of patients. Side effects of OFS mimic menopausal symptoms, including hot flushes, sweats, weight gain, and sexual dysfunction, which may negatively impact quality of life (QoL). Aims of the Take Care Project are the education of physicians and patients to have all the information (medical and nonmedical) they need to manage menopausal symptoms by distributing educational materials useful to face menopause. Four different areas have been identified by surveys conducted among physicians and young patients: for each area, interventions and tools have been elaborated by a doctor and nonphysician professionals of these identified areas, to offer the widest information available. Clinical and practical suggestions have been provided. Based on the evidence given, we strongly suggest setting up a multidisciplinary team for the treatment planning of young patients with BC, which could help patients to face and manage their new menopause condition. The reduction of side effects and the improvement in QoL should be the best ally to treat young patients with BC.

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Conclusion: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Conclusion: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.

OBJECTIVE: To describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls. METHODS: Consecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo Hospital, Monza and San Matteo Hospital, Pavia) were considered in this analysis and compared with controls who had the same surgical procedure for benign conditions. Frequency of p53 signature, serous tubal intraepithelial carcinoma, and high-grade serous ovarian cancer were compared between the two groups. RESULTS: A total of 194 women with pathogenic BRCA1/2 mutations underwent prophylactic salpingo-oophorectomy. Of these, 138 women (71%) had a completely negative histological examination, while in 56 (29%) patients an ovarian or tubal alteration was reported. Among controls, 84% of patients had a p53wt signature, while 16% had a p53 signature. There was no difference in the frequency of a p53 signature between cases and controls; however, women with BRCA1/2 mutations were more likely to have pre-malignant or invasive alterations of tubal or ovarian epithelium (p=0.015). Among mutation carriers, older age both at genetic testing and at surgery was associated with an increased risk of having malignancies (OR=1.07, p=0.006 and OR=1.08, p=0.004, respectively). The risk of malignancy seems to be increased in patients with a familial history of high-grade serous ovarian cancer. Previous therapy with tamoxifen was significantly more frequent in patients with malignant lesions (40.0% vs 21.3%, p=0.006). CONCLUSION: We found that a p53 signature is a frequent finding both in BRCA1/2 mutation carriers and in controls, while pre-invasive and invasive lesions are more frequent in BRCA1/2 mutation carriers. Genetic and clinical characteristics are likely to affect the progression to malignancy.

Activation of the checkpoint protein Tel1 requires the Mre11-Rad50-Xrs2 (MRX) complex, which recruits Tel1 at DNA double-strand breaks (DSBs) through direct interaction between Tel1 and Xrs2. However, in vitro Tel1 activation by MRX requires ATP binding to Rad50, suggesting a role also for the MR subcomplex in Tel1 activation. Here we describe two separation-of-functions alleles, mre11-S499P and rad50-A78T, which we show to specifically affect Tel1 activation without impairing MRX functions in DSB repair. Both Mre11-S499P and Rad50-A78T reduce Tel1-MRX interaction leading to poor Tel1 association at DSBs and consequent loss of Tel1 activation. The Mre11-S499P variant reduces Mre11-Rad50 interaction, suggesting an important role for MR complex formation in Tel1 activation. Molecular dynamics simulations show that the wild type MR subcomplex bound to ATP lingers in a tightly 'closed' conformation, while ADP presence leads to the destabilization of Rad50 dimer and of Mre11-Rad50 association, both events being required for MR conformational transition to an open state. By contrast, MRA78T undertakes complex opening even if Rad50 is bound to ATP, indicating that defective Tel1 activation caused by MRA78T results from destabilization of the ATP-bound conformational state.

Objective: Little is known about the process of becoming a mother in women who experienced a breast cancer diagnosis (BC). In this qualitative study, we investigated maternal representations in pregnant women with experience of BC and those with no oncological history. Methods: A total of 38 women were recruited, 19 women who experienced a BC diagnosis and 19 who had not. To explore maternal representations, semi-structured interviews were conducted and analysed through thematic analysis. Results: Four main themes were identified: fears and worries, meaning of motherhood, mother–foetus relationship and partner support. Across themes, differences between primiparous and multiparous are reported. Women with gestational breast cancer (GBC) described fear for their own and their child's survival. Women with previous BC recall contrasting emotions. All women with experience of BC perceived breastfeeding as fundamental and inability to do so provoked worry. Relationship with the partner was considered central, while healthy women were projected towards the future triadic relationship. Conclusions: Finding a mental space during pregnancy for the representation of the future child could be hard for women with GBC. Dissimilarities in the experience of motherhood in cancer patients provide insight into psychological aspects that should be taken into account in clinical practice.

The evolutionarily conserved Mre11–Rad50–Xrs2 (MRX) complex cooperates with the Sae2 protein in initiating resection of DNA double-strand breaks (DSBs) and in maintaining the DSB ends tethered to each other for their accurate repair. How these MRX–Sae2 functions contribute to DNA damage resistance is not understood. By taking advantage of mre11 alleles that suppress the hypersensitivity of sae2∆ cells to genotoxic agents, we have recently found that Mre11 can be divided in two structurally distinct domains that support resistance to genotoxic agents by mediating different processes. While the Mre11 N-terminal domain impacts on the resection activity of long-range resection nucleases by mediating MRX and Tel1/ATM association to DNA DSBs, the C-terminus influences the MRX-tethering activity by its virtue to interact with Rad50. Given the evolutionary conservation of the MRX complex, our results have implications for understanding the consequences of its dysfunctions in human diseases

Young cancer survivors often wish to bear a child after oncological treatments, as they might not have started or completed their families. As young cancer survivors have a higher risk of developing psychological difficulties, this study investigated whether there were significant differences in psychological aspects between pregnant women who received a cancer diagnosis in the past and pregnant women without a history of cancer. A total of 123 pregnant women, of which 36 were cancer survivors and 87 women without a history of cancer, were recruited during their last trimester at different hospitals in Northern Italy. Patients were asked to complete a socio-demographic profile and questionnaires measuring mood states, post-traumatic symptoms, centrality of the pregnancy and cancer event, quality of life, and prenatal attachment. Cancer survivors had significantly higher levels of PTSD symptoms, perceived pregnancy as more central to their identity and life story, perceived lower quality of life and had lower intensity of prenatal attachment compared with the control group. Centrality of the cancer event did not correlate with any psychological variables. Preliminary results suggest that a past cancer diagnosis can influence the mother’s psychological functioning and the development of the relationship with their child.

Objective. About 30% of Adult type granulosa cell tumors of the ovary (AGCTs) are diagnosed in fertile age. In stage I, conservative surgery (fertility-sparing surgery, FSS), either unilateral salpingo-oophorectomy (USO) or cystectomy are possible options. The aim of this study is to compare oncological outcomes of FSS and radical surgery (RS) in apparently stage I AGCTs treated within the MITO group (Multicenter Italian Trials in Ovarian cancer). Methods. Survival curves were calculated using the Kaplan-Meiermethod and comparedwith log-rank test. The role of clinicopathological variables as prognostic factors for survival was assessed using Cox's regression. Results. Two-hundred and twenty-nine patients were included; 32.6% received FSS, 67.4% RS. In the FSS group, 62.8% underwent USO, 16.7% cystectomy, 20.5% cystectomy followed by USO. After a median follow up of 84 months, median DFS was significantly worse in the FSS-group (10 yr DFS 50% vs 74%, in FSS and RS group, p = 0.006). No significant difference was detected between RS and USO (10 yr DFS 75% vs 70%, p = 0.5). Cystectomy-group showed a significantly worse DFS compared to USO (10 yr DFS 16% vs 70%, p b 0.001). Patients receiving cystectomy and subsequent USO showed a better prognosis, even though significantly worse compared to USO (10 yr DFS 41% vs 70%, p=0.05). Between FSS and RS, no difference in OS was detected. Atmultivariate analysis,FIGO stage IC and cystectomy retained significant predictive value for worse survival. Conclusions. This study supports the oncological safety of FSS in stage I AGCTs, provided that cystectomy is avoided; USO should be the preferred approach

Homologous recombination is triggered by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection requires the Mre11-Rad50-Xrs2 (MRX) complex, which promotes the activity of Exo1 nuclease through a poorly understood mechanism. Here, we describe the Mre11-R10T mutant variant that accelerates DSB resection compared to wild-type Mre11 by potentiating Exo1-mediated processing. This increased Exo1 resection activity leads to a decreased association of the Ku complex to DSBs and an enhanced DSB resection in G1, indicating that Exo1 has a direct function in preventing Ku association with DSBs. Molecular dynamics simulations show that rotation of the Mre11 capping domains is able to induce unwinding of double-strand DNA (dsDNA). The R10T substitution causes altered orientation of the Mre11 capping domain that leads to persistent melting of the dsDNA end. We propose that MRX creates a specific DNA end structure that promotes Exo1 resection activity by facilitating the persistence of this nuclease on the DSB ends, uncovering a novel MRX function in DSB resection

Objective: Surgery represents the mainstay of treatment of stage I adult type granulosa cell tumors of the ovary (AGCTs). Because of the rarity and indolent course of the disease, no prospective trials are available. Open surgery has long been considered the traditional approach; oncological safety of laparoscopy is only supported by small series or case reports. The aim of this study was to compare the oncological outcomes between laparoscopic and open surgery in stage I AGCTs treated within the MITO (Multicenter Italian Trials in Ovarian cancer) Group. Methods: Data from patients with stage I AGCTs were retrospectively collected. Clinicopathological features were evaluated for association with relapse and death. Survival curves were calculated using the Kaplan-Meier method and compared with the log-rank test. The role of clinicopathological variables as prognostic factors for survival was evaluated using Cox's regression model. Results: 223 patients were identified. Stage 1A, 1B and 1C were 61.5%, 1.3% and 29.6% respectively. 7.6% were apparently stage I. Surgical approach was laparoscopic for 93 patients (41.7%) and open for 130 (58.3%). 5-years DFS was 84% and 82%, 10-years DFS was 68% and 64% for the laparoscopic and open-group (p = 0.6).5-years OS was 100% and 99%, 10 years OS was 98% and 97% for the laparoscopic and open-surgery group (p = 0.8). At multivariate analyses stage IC, incomplete staging, site of primary surgery retained significant prognostic value. Conclusion: The present study suggests that surgical route does not affect the oncological safety of patients with stage I AGCTs, with comparable outcomes between laparoscopic and open approach.

Mec1ATR mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATR response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.

Telomeric DNA consists of repetitive G-rich sequences that terminate with a 3 ́-ended single stranded overhang (G-tail), which is important for telomere extension by telomerase. Several proteins, including the CST complex, are necessary to maintain telomere structure and length in both yeast and mammals. Emerging evidence indicates that RNA processing factors play critical, yet poorly understood, roles in telomere metabolism. Here, we show that the lack of the RNA processing proteins Xrn1 or Rrp6 partially bypasses the requirement for the CST component Cdc13 in telomere protection by attenuating the activation of the DNA damage checkpoint. Xrn1 is necessary for checkpoint activation upon telomere uncapping because it promotes the generation of single-stranded DNA. Moreover, Xrn1 maintains telomere length by promoting the association of Cdc13 to telomeres independently of ssDNA generation and exerts this function by downregulating the transcript encoding the telomerase inhibitor Rif1. These findings reveal novel roles for RNA processing proteins in the regulation of telomere metabolism with implications for genome stability in eukaryotes

Background: Surgery followed by platinum-based chemotherapy is the standard of care for MOGCTs, except for stage IA dysgerminoma and stage IA grade 1 immature teratoma where surveillance only is recommended. The role of adjuvant chemotherapy and surgical staging is debated. Patients and methods: Data from 144 patients with stage I MOGTs were collected among MITO centers (Multicenter Italian Trials in Ovarian Cancer) and analyzed. Results: Fifty-five (38.2%) patients were affected by dysgerminomas, 49 (34%) by immature teratomas, 26 (18.1%) by yolk sac tumors and 14 (9.7%) by mixed tumors. Seventy-three (50.7%) patients receive surgery plus chemotherapy, while 71 (49.3%) patients underwent surgery alone. The latter group included 32 dysgerminomas (14 IA-13 Ix, 3 IB, and 2 IC), 34 immature teratomas (20 1A-13 IA grade 1, 6 Ix, 1 IB, and 7 IC), 4 mixed tumors and 1 yolk sac tumor. Forty-four patients did not received chemotherapy, even if it would have been indicated by recommended approach. 94 (65.3%) patients received peritoneal surgical staging. Twenty-three (15.9%) developed a recurrence. Incomplete surgical staging was associated with recurrence (P < 0.05; OR 2.37) at Cox regression analysis. Seven patients died. Four patients were affected by yolk sac tumors, two by mixed tumors and one by immature teratoma. Five patients died for disease, one for acute leukemia and one for suicide. Prognostic parameter analyses showed that yolk sac component is a predictor for survival (P < 0.05). Five-years OS rates were 96.8% and 88.7% in the surgically staged and the incomplete staged group, respectively, while 93.8% and 94.1% in the standard treatment and in the surveillance group, respectively. Conclusions: This study shows that surveillance seems not to affect survival; chemotherapy should be reserved for relapse resulting in high cure rate. Incomplete peritoneal surgical staging is associated with recurrence. Yolk sac histology worsens the prognosis.

DNA double-strand breaks (DSBs) pose a serious threat to genome stability and cell survival. Cells possess mechanisms that recognize DSBs and promote their repair through either homologous recombination (HR) or nonhomologous end joining (NHEJ). The evolutionarily conserved Mre11-Rad50-Xrs2 (MRX) complex plays a central role in the cellular response to DSBs, as it is implicated in controlling end resection and in maintaining the DSB ends tethered to each other. Furthermore, it is responsible for DSB signaling by activating the checkpoint kinase Tel1 that, in turn, supports MRX function in a positive feedback loop. The present review focuses mainly on recent works in the budding yeast Saccharomyces cerevisiae to highlight structure and regulation of MRX as well as its interplays with Tel1.

DNA double-strand breaks (DSBs) are a nasty form of damage that needs to be repaired to ensure genome stability. The DSB ends can undergo a strand-biased nucleolytic processing (resection) to generate 3′-ended single-stranded DNA (ssDNA) that channels DSB repair into homologous recombination. Generation of ssDNA also triggers the activation of the DNA damage checkpoint, which couples cell cycle progression with DSB repair. The checkpoint response is intimately linked to DSB resection, as some checkpoint proteins regulate the resection process. The present review will highlight recent works on the mechanism and regulation of DSB resection and its interplays with checkpoint activation/inactivation in budding yeast.

Cyclin-dependent kinase (Cdk1) activity is required for mitotic entry, and this event is restrained by an inhibitory phosphorylation of the catalytic subunit Cdc28 on a conserved tyrosine (Tyr19). This modification is brought about by the protein kinase Swe1 that inhibits Cdk1 activation thus blocking mitotic entry. Swe1 levels are regulated during the cell cycle, and they decrease during G2/M concomitantly to Cdk1 activation, which drives entry into mitosis. However, after mitotic entry, a pool of Swe1 persists, and we collected evidence that it is involved in controlling mitotic spindle elongation. We also describe that the protein phosphatase Cdc14 is implicated in Swe1 regulation; in fact, we observed that Swe1 dephosphorylation in vivo depends on Cdc14 that, in turn, is able to control its subcellular localization. In addition we show that the lack of Swe1 causes premature mitotic spindle elongation and that high levels of Swe1 block mitotic spindle elongation, indicating that Swe1 inhibits this process. Importantly, these effects are not dependent upon the role of in Cdk1 inhibition. These data fit into a model in which Cdc14 binds and inhibits Swe1 to allow timely mitotic spindle elongation.

Homologous recombination requires nucleolytic degradation (resection) of DNA double-strand break (DSB) ends. In Saccharomyces cerevisiae, the MRX complex and Sae2 are involved in the onset of DSB resection, whereas extensive resection requires Exo1 and the concerted action of Dna2 and Sgs1. Here, we show that the checkpoint protein Rad9 limits the action of Sgs1/Dna2 in DSB resection by inhibiting Sgs1 binding/persistence at the DSB ends. When inhibition by Rad9 is abolished by the Sgs1-ss mutant variant or by deletion of RAD9, the requirement for Sae2 and functional MRX in DSB resection is reduced. These results provide new insights into how early and long-range resection is coordinated. Synopsis The checkpoint protein Rad9 inhibits the Sgs1/Dna2 long-range resection machinery and thereby increases the requirement for MRX/Sae2 activities in DSB resection. The Sgs1-ss mutant variant suppresses the sensitivity to DNA damaging agents and the resection defect of sae2 cells. Rad9 limits the action of Sgs1/Dna2 in DSB resection by inhibiting Sgs1 binding/persistence at the DSB ends. The escape of Sgs1 from Rad9 inhibition reduces the requirement for Sae2 and functional MRX in DSB resection. The checkpoint protein Rad9 inhibits the Sgs1/Dna2 long-range resection machinery and thereby increases the requirement for MRX-Sae2 activities in DSB resection.

La citochinesi è quel processo regolato nel tempo e nello spazio tramite cui, dopo la segregazione dei cromosomi, le cellule eucariotiche dividono il loro citoplasma e le membrane per formare due cellule figlie indipendenti l’una dall’altra. Nel lievito gemmante Saccharomyces cerevisiae la citochinesi è promossa da vie finemente regolate che coordinano la divisione cellulare con la divisione nucleare al fine di garantire la stabilità genetica di cellule in crescita. Queste vie promuovono la contrazione dell’anello di actomiosina (AC) accoppiandola rispettivamente con la costrizione della membrana plasmatica e con la deposizione centripeta del setto primario (SP). Le vie che portano alla citochinesi sono parzialmente ridondanti e la loro contemporanea inattivazione causa un blocco della citochinesi e morte cellulare. Nelle cellule animali, il piano di divisione è specificato dal posizionamento del fuso mitotico e la citochinesi avviene grazie alla contrazione dell’anello di actomiosina, seguita dall’invaginazione della membrana plasmatica. In S. cerevisiae, il primo passo verso la citochinesi è l’assemblaggio di un anello rigido di septine attorno al collo della gemma contemporaneamente all’emissione della stessa, non appena le cellule entrano in fase S, definendo la posizione in cui avrà luogo la costrizione tra la cellula madre e la figlia in seguito all’uscita dalla mitosi. L’anello di septine funge da piattaforma di legame, al collo della gemma, per diverse proteine tra cui la catena pesante della miosina di tipo II, Myo1. Myo1 forma un anello al sito di emissione della gemma all’inizio della fase S in modo dipendente dalle septine. Alla fine dell’anafase un anello di actina si sovrappone con quello di Myo1 a generare il risultante anello di actomiosina la cui contrazione è strettamente accoppiata alla deposizione del setto primario. L’anello di septine permette la localizzazione anche di Iqg1 che, insieme a Bni1, è importante per il reclutamento dell’act, Cytokinesis is the spatially and temporally regulated process by which, after chromosome segregation, eukaryotic cells divide their cytoplasm and membranes to produce two daughter cells independent of each other. In the budding yeast Saccharomyces cerevisiae cytokinesis is driven by tightly regulated pathways that coordinate cell division with nuclear division to ensure the genetic stability during cell growth. These ways promote actomyosin ring (AMR) contraction coupled to plasma membrane constriction and to centripetal deposition of the primary septum, respectively. These pathways can partially substitute for each other, but their concomitant inactivation leads to cytokinesis block and cell death. In animal cells, the division plane is defined by the central spindle positioning and cytokinesis occurs through the contraction of the AMR, followed by the membrane furrowing. In S. cerevisiae, the first step towards cytokinesis is the assembly of a rigid septin ring, which forms at the bud neck concomitantly with bud emergence as soon as cells enter S phase and marks the position where constriction between mother and daughter cell will take place at the end of mitosis. The septin ring acts as a scaffold for the recruitment other proteins, among which Myo1, the heavy chain of the type II miosin. Myo1 forms a ring at the site of bud emergence at the onset of S phase in a septin-dependent manner. At the end of anaphase, an actin ring overlaps with that of Myo1 and the resulting contractile actomyosin ring drives primary septum deposition. The septin ring also recruits Iqg1 which is important, together with Bni1, for actin recruitment at the bud neck, Cyk3, required for proper synthesis of the septum, and Hof1, which is phosphorylated in telophase and colocalizes with the actomyosin ring during cytokinesis. The subsequent degradation of Hof1 allows efficient AMR contraction and cell separation. During mitotic exit, Chs2 localizes at the cell division site, where it drives

In budding yeast, the septins are assembled into structures that undergo dramatic changes during the cell cycle. The molecular mechanisms that drive these remodelings are not fully uncovered. In this study we describe a characterization of Vhs2, a nonessential protein that revealed to be a new player in septin dynamics. In particular, we report that Vhs2 is important to maintain the stability of the double septin ring structure until telophase. In addition, we show that Vhs2 undergoes multiple phosphorylations during the cell cycle, being phosphorylated during S phase until nuclear division and dephosphorylated just before cell division. Importantly we report that cyclin-dependent protein kinase Cdk1 and protein phosphatase Cdc14 control these Vhs2 post-translational modifications. These results reveal that Vhs2 is a novel Cdc14 substrate that is involved in the control of septin organization.