Protection of nascent DNA at stalled replication forks is mediated by phosphorylation of RIF1 intrinsically disordered region

Acknowledgements We thank all members of the Di Virgilio lab for their feedback and discussion; V Delgado-Benito (Di Virgilio lab, MDC, Berlin) for her contribution to the project development; L Keller (Di Virgilio lab, MDC, Berlin) for support with cloning, mutagenesis, and mice genotyping; C Brischetto (Scheidereit Lab, MDC, Berlin) for assistance with confocal microscopy; Aberdeen Proteomics facility (University of Aberdeen) for the mass spec analysis of Aph-induced hRIF1 phosphorylation; and the MDC FACS Core Facility and Dr. HP Rahn for support with cell sorting. Aliquots of ATRi and ATMi were gener- ously provided by AG Henssen (MDC and ECRC, Berlin). Figures 1B and D, 2A, and 4C contain items created with BioRender.com. This work was supported by ERC grant 638897 (to MDV), the Helmholtz- Gemeinschaft Zukunftsthema 'Immunology and Inflammation' ZT-0027 (to MDV), P41 GM109824 and P41 GM103314 (to BTC), and Cancer Research UK awards C1445/A19059 and DRCPGM\100,013 (to ADD and SH).Peer reviewe

An Integrative Computational Approach for Prioritization of Genomic Variants

An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.</p

Entschlüsselung des Mechanismus von RIF1 zur Aufrechterhaltung der DNA-Replikations-assoziierten Genomstabilität

Timely and accurate genome duplication is essential to maintain genome integrity and cell survival. DNA replication-associated damage is one of the leading causes of genome instability and a precursor for carcinogenesis. The DNA replication fork (RF), the site for assembly of replication proteins, encounters a variety of obstacles, which slow or stall its progression, a process termed replication stress. Cells have evolved a number of mechanisms to stabilize stalled forks and to ensure replication restart and timely completion. However, during chronic stress, forks can no longer be stabilized and collapse, creating toxic DNA double-strand breaks (DSB). These DSBs, when left unrepaired, can lead to chromosomal rearrangements and promote genomic instability. RIF1, a multifunctional protein, is critical not only to promote fork stability and to ensure that replication is completed, but also to repair DSBs in the event of prolonged replication stress. While modulation of DSB repair pathways represents one of the resistance mechanisms to chemotherapeutic drugs, maintenance of fork stability is critical to prevent carcinogenesis from developing in the first place. Here, we have identified novel post translational modifications of RIF1 that are critical for its role in the maintenance of genome stability. Specifically, phosphorylation of a conserved cluster of SQ sites in RIF1 modulates its role in fork stabilization while being dispensable for its function in DSB repair

Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged and NPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin&ndash;KMT2A interaction affects the proleukemogenic HOX/MEIS transcription program. This disruption leads to the differentiation of KMT2Ar and NPM1-m AML cells. Small molecular inhibitors of the menin&ndash;KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review

Adoption of Mobile ERP in Educational Environment

The objective of this research paper is to investigate the intention to use mobile ERP under the effect of computer self-efficacy and system security at a university setting. Mobile ERP, a business software that integrates core business functions into a single system, has been increasingly penetrating the ERP market with promising benefits like real-time data availability and sharing, greater productivity, and competitive advantage, but to the best of the author's knowledge, there is no study that has investigated its usage intention among a traditional-ERP organization. The updated DeLone and McLean IS success model with its three quality factors is employed in this study as a theoretical framework and extended with system security and computer self-efficacy to examine the adoption of mobile ERP as an emerging phenomenon. With a sample of 347 university students, SEM results suggest that service quality, system security, and computer self-efficacy are significant determinants of individuals' intention towards using mobile ERP.</p