Characterization of age-associated gene expression changes in mouse sweat glands.

Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding 'core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the 'core secretory' category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.

Application of Amorphous and Nanocrystalline Soft Magnetic Materials in Balanced-Force-Type Electromagnetic Relay.

The magnetic properties of soft magnetic materials, including their saturation magnetic induction strength and permeability, significantly affect the dynamic characteristics of electromagnetic relays. However, the soft materials most commonly used for relays in the magnetic conductive components of electromagnetic systems, such as electrical pure iron, limit further relay design improvement and optimization to a certain extent. Thus, this paper proposes the use of amorphous and nanocrystalline soft magnetic materials with good high-frequency magnetic properties in magnetic circuits. A wavelet analysis was conducted on the high-frequency components of the coil current while the relay operated, and the corresponding magnetic materials were selected. Considering the challenges in processing amorphous and nanocrystalline materials and collecting test data for the accuracy verification of simulation methods, we prepared a scaled-up prototype for use in dynamic characteristic tests. The simulation method was improved, yielding more accurate simulation results regarding the relay's dynamic characteristics. On this basis, six replacement schemes using amorphous and nanocrystalline materials were considered. The test results proved that this application could improve the relay's dynamic characteristics. Finally, a full-size sample with an iron core consisting of nanocrystalline alloy 1K107B was prepared, and the conclusions were verified in tests.

Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity.

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we generated a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.

RNA-binding protein Nocte regulates Drosophila development by promoting translation reinitiation on mRNAs with long upstream open reading frames.

RNA-binding proteins (RBPs) with intrinsically disordered regions (IDRs) are linked to multiple human disorders, but their mechanisms of action remain unclear. Here, we report that one such protein, Nocte, is essential for Drosophila eye development by regulating a critical gene expression cascade at translational level. Knockout of nocte in flies leads to lethality, and its eye-specific depletion impairs eye size and morphology. Nocte preferentially enhances translation of mRNAs with long upstream open reading frames (uORFs). One of the key Nocte targets, glass mRNA, encodes a transcription factor critical for differentiation of photoreceptor neurons and accessory cells, and re-expression of Glass largely rescued the eye defects caused by Nocte depletion. Mechanistically, Nocte counteracts long uORF-mediated translational suppression by promoting translation reinitiation downstream of the uORF. Nocte interacts with translation factors eIF3 and Rack1 through its BAT2 domain, and a Nocte mutant lacking this domain fails to promote translation of glass mRNA. Notably, de novo mutations of human orthologs of Nocte have been detected in schizophrenia patients. Our data suggest that Nocte family of proteins can promote translation reinitiation to overcome long uORFs-mediated translational suppression, and disruption of this function can lead to developmental defects and neurological disorders.

Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity.

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex in animals that can alter the topology of both DNA and RNA. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impairments in cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal shorten-memory and learning, and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we built a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive impairment and psychiatric disorders.

A dual-activity topoisomerase complex promotes both transcriptional activation and repression in response to starvation.

Topoisomerases are required to release topological stress generated by RNA polymerase II (RNAPII) during transcription. Here, we show that in response to starvation, the complex of topoisomerase 3b (TOP3B) and TDRD3 can enhance not only transcriptional activation, but also repression, which mimics other topoisomerases that can also alter transcription in both directions. The genes enhanced by TOP3B-TDRD3 are enriched with long and highly-expressed ones, which are also preferentially stimulated by other topoisomerases, suggesting that different topoisomerases may recognize their targets through a similar mechanism. Specifically, human HCT116 cells individually inactivated for TOP3B, TDRD3 or TOP3B topoisomerase activity, exhibit similarly disrupted transcription for both starvation-activated genes (SAGs) and starvation-repressed genes (SRGs). Responding to starvation, both TOP3B-TDRD3 and the elongating form of RNAPII exhibit concomitantly increased binding to TOP3B-dependent SAGs, at binding sites that overlap. Notably, TOP3B inactivation decreases the binding of elongating RNAPII to TOP3B-dependent SAGs while increased it to SRGs. Furthermore, TOP3B-ablated cells display reduced transcription of several autophagy-associated genes and autophagy per se. Our data suggest that TOP3B-TDRD3 can promote both transcriptional activation and repression by regulating RNAPII distribution. In addition, the findings that it can facilitate autophagy may account for the shortened lifespan of Top3b-KO mice.

Molecular basis of JAK2 H608Y and H608N mutations in the pathology of acute myeloid leukemia.

Risk-stratification of acute myeloid leukemia (AML) based on (cyto)genetic aberrations, including hotspot mutations, deletions and point mutations have evolved substantially in recent years. With the development of next-generation sequence technology, more and more novel mutations in the AML were identified. Thus, to unravel roles and mechanism of novel mutations would improve prognostic and predictive abilities. In this study, two novel germline JAK2 His608Tyr (H608Y) and His608Asn (H608N) mutations were identified and the molecular basis of these mutations in the leukemiagenesis of AML was elucidated. Our results indicated that JAK2 H608Y and H608N mutations disrupted the hydrogen bond between Q656 and H608 which reduced the JH2 domain's activity and abolished interactions between JH1 and JH2 domains, forced JAK2 into the active conformation, facilitated the entrance of substrates and thus caused JAK2 hyperactivation. Further studies suggested that JAK2 H608Y and H608N mutations enhanced the cell proliferation and inhibited the differentiation of Ba/F3 and MV4-11 cells via activating the JAK2-STAT5 signaling pathway. Moreover, rescue experiments demonstrated that mutations repaired the hydrogen bond between Q656 and H608 displayed opposite results. Thus, this study revealed the molecular basis of JAK2 H608Y and H608N mutations in the pathology of AML.

Topoisomerase 3b is dispensable for replication of a positive-sense RNA virus--murine coronavirus.

A recent study demonstrated that a DNA-RNA dual-activity topoisomerase complex, TOP3B-TDRD3, is required for normal replication of positive-sense RNA viruses, including several human flaviviruses and coronaviruses; and the authors proposed that TOP3B is a target of antiviral drugs. Here we examined this hypothesis by investigating whether inactivation of Top3b can inhibit the replication of a mouse coronavirus, MHV, using cell lines and mice that are inactivated of Top3b or Tdrd3. We found that Top3b-KO or Tdrd3-KO cell lines generated by different CRISPR-CAS9 guide RNAs have variable effects on MHV replication. In addition, we did not find significant changes of MHV replication in brains or lungs in Top3B-KO mice. Moreover, immunostaining showed that Top3b proteins are not co-localized with MHV replication complexes but rather, localized in stress granules in the MHV-infected cells. Our results suggest that Top3b does not have a universal role in promoting replication of positive-sense RNA virus, and cautions should be taken when targeting it to develop anti-viral drugs.

Effects of the PLK4 inhibitor Centrinone on the biological behaviors of acute myeloid leukemia cell lines.

Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, is frequently overexpressed in cancer cells. However, roles and the mechanism of PLK4 in the leukemiagenesis of acute myeloid leukemia (AML) remain unclear. In this study, the PLK4 inhibitor Centrinone and the shRNA knockdown were used to investigate roles and the mechanism of PLK4 in the leukemiagenesis of AML. Our results indicated that Centrinone inhibited the proliferation of AML cells in a dose- and time-dependent manner via reduced the expression of PLK4 both in the protein and mRNA levels. Moreover, colony formation assay revealed that Centrinone reduced the number and the size of the AML colonies. Centrinone induced AML cell apoptosis by increasing the activation of Caspase-3/poly ADP-ribose polymerase (PARP). Notably, Centrinone caused the G2/M phase cell cycle arrest by decreasing the expression of cell cycle-related proteins such as Cyclin A2, Cyclin B1, and Cyclin-dependent kinase 1 (CDK1). Consistent with above results, knockdown the expression of PLK4 also inhibited cell proliferation and colony formation, induced cell apoptosis, and caused G2/M phase cell cycle arrest without affecting cell differentiation. All in all, this study suggested that PLK4 inhibited the progression of AML in vitro, and these results herein may provide clues in roles of PLK4 in the leukemiagenesis of AML.

Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines.

PURPOSE: FLT3 mutations occurred in approximately one third of patients with acute myeloid leukemia (AML). FLT3-ITD mutations caused the constitutive activation of the RAS/MAPK signaling pathway. Ribosomal S6 Kinases (RSKs) were serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. However, roles and mechanisms of RSKs inhibitor LJH-685, and combinational effects of LJH-685 and FLT3 inhibitor FF-10101 on AML cells were till unclear. METHODS: Cell viability assay, CFSE assay, RT-qPCR, Colony formation assay, PI stain, Annexin-V/7-AAD double stain, Western blot, and Xenogeneic transplantation methods were used to used to investigate roles and mechanisms of LJH-685 in the leukemogenesis of AML. RESULTS: LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations. Moreover, in vivo experiments also indicated that LJH-685 combined with FF-10101 or Daunorubicin prolonged the survival time of NSG mice and reduced the leukemogenesis of AML. CONCLUSION: Thus, these observations demonstrated combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 showed synergism anti-leukemia effects in AML cell lines with FLT3-ITD mutations via inhibiting MAPK-RSKs-YB-1 pathway and provided new targets for therapeutic intervention especially for AML with FLT3-ITD mutations and Daunorubicin-resistant AML.

A dual-activity topoisomerase complex regulates mRNA translation and turnover.

Topoisomerase 3ß (TOP3B) and TDRD3 form a dual-activity topoisomerase complex that interacts with FMRP and can change the topology of both DNA and RNA. Here, we investigated the post-transcriptional influence of TOP3B and associated proteins on mRNA translation and turnover. First, we discovered that in human HCT116 colon cancer cells, knock-out (KO) of TOP3B had similar effects on mRNA turnover and translation as did TDRD3-KO, while FMRP-KO resulted in rather distinct effects, indicating that TOP3B had stronger coordination with TDRD3 than FMRP in mRNA regulation. Second, we identified TOP3B-bound mRNAs in HCT116 cells; we found that while TOP3B did not directly influence the stability or translation of most TOP3B target mRNAs, it stabilized a subset of target mRNAs but had a more complex effect on translation-enhancing for some mRNAs whereas reducing for others. Interestingly, a point mutation that specifically disrupted TOP3B catalytic activity only partially recapitulated the effects of TOP3B-KO on mRNA stability and translation, suggesting that the impact of TOP3B on target mRNAs is partly linked to its ability to change topology of mRNAs. Collectively, our data suggest that TOP3B-TDRD3 can regulate mRNA translation and turnover by mechanisms that are dependent and independent of topoisomerase activity.

[Calnexin (CNX) enhances the killing effect of CD8+ T cells on colorectal cancer cells by promoting MHC I expression].

Objective To investigate the killing effect and molecular mechanism of aberrant expression of calnexin (CNX) in the colorectal cancer (CRC) on the CD8+ T immune cells. Methods Immunohistochemistry was used to detect CNX protein level in 102 pairs of CRC cancer and adjacent non-cancerous tissues. Western blotting was employed to examine the protein expression of MHC I in the HCT-15 cells overexpressed with CNX or in the SW480 cells whose CNX expressions were knockdown by siRNA. Murine CD8+ T cells isolated from the spleen were cocultured with CT-26 murine CRC cells infected with lentivirus-mediated CNX overexpression. The killing effect of CD8+ T cells on CT-26 cells was determined by cytotoxicity kit. The secretion of interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) in the culture medium were examined by ELISA. Results The protein level of CNX in colorectal cancer tissues were significantly lower than that in non-cancerous tissues. CNX overexpressed in HCT-15 cells was upregulated and CNX knockdown in SW480 cells downregulated the MHC I expression in these cells. Furthermore, the overexpression of CNX could not only enhance the killing effect of CD8+ T cells on CT-26 cells, but also promote the secretion of IFN-γ and TNF-α from these cells. Conclusion CNX can enhance the killing potential of CD8+ T cells on tumor cells through upregulating the MHC I expression in colorectal cancer cells.

Risk Assessment of High-Speed Rail Projects: A Risk Coupling Model Based on System Dynamics.

Due to their characteristics and multiple objectives, high-speed rail (HSR) projects carry more complex risks than conventional projects and high correlation and conductivity are among the associated risk factors. Previous risk assessment frameworks for rail infrastructure have ignored the effects of risk interactions that inflate risk levels, namely, risk coupling effects. Based on a system dynamics method, this paper develops a risk coupling model for HSR project risk assessments. A risk factor list is established from a literature review, and relationships analysed using a case study and expert interviews. System dynamics equations are constructed and their parameters obtained by expert evaluations of risk factors. The proposed model is applied to a real-world HSR project to demonstrate it in detail. The model can evaluate the risk levels of HSR projects during a simulation period. In particular, it can identify the key coupling effects that are the main increased risk. It provides a significant resource, using which HSR project managers can identify and mitigate risks.

Topoisomerase 3ß knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity.

Topoisomerase 3ß (Top3ß) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3ß mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3ß knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3ß is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3ß deletion causes cognitive impairment and psychiatric disorders.

Mesoporous cobalt monoxide-supported platinum nanoparticles: Superior catalysts for the oxidative removal of benzene.

Mesoporous Co3O4 (meso-Co3O4)-supported Pt (0.53 wt.% Pt/meso-Co3O4) was synthesized via the KIT-6-templating and polyvinyl alcohol (PVA)-assisted reduction routes. Mesoporous CoO (meso-CoO) was fabricated through in situ reduction of meso-Co3O4 with glycerol, and the 0.18-0.69 wt.% Pt/meso-CoO samples were generated by the PVA-assisted reduction method. Meso-Co3O4 and meso-CoO were of cubic crystal structure and the Pt nanoparticles (NPs) with a uniform size of ca. 2 nm were well distributed on the meso-Co3O4 or meso-CoO surface. The 0.56 wt% Pt/meso-CoO (0.56Pt/meso-CoO) sample performed the best in benzene combustion (T50% = 156 °C and T90% = 186 °C at a space velocity of 80,000 mL/(g h)). Introducing water vapor or CO2 with a certain concentration led to partial deactivation of 0.56 Pt/meso-CoO and such a deactivation was reversible. We think that the superior catalytic activity of 0.56 Pt/meso-CoO was intimately related to its good oxygen activation and benzene adsorption ability.

Topoisomerase 3ß interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila.

Topoisomerases solve topological problems during DNA metabolism, but whether they participate in RNA metabolism remains unclear. Top3ß represents a family of topoisomerases carrying activities for both DNA and RNA. Here we show that in Drosophila, Top3ß interacts biochemically and genetically with the RNAi-induced silencing complex (RISC) containing AGO2, p68 RNA helicase, and FMRP. Top3ß and RISC mutants are similarly defective in heterochromatin formation and transcriptional silencing by position-effect variegation assay. Moreover, both Top3ß and AGO2 mutants exhibit reduced levels of heterochromatin protein HP1 in heterochromatin. Furthermore, expression of several genes and transposable elements in heterochromatin is increased in the Top3ß mutant. Notably, Top3ß mutants defective in either RNA binding or catalytic activity are deficient in promoting HP1 recruitment and silencing of transposable elements. Our data suggest that Top3ß may act as an RNA topoisomerase in siRNA-guided heterochromatin formation and transcriptional silencing.

Microstructure design of lightweight fibrous material acting as a layered damper for a vibrating stiff panel.

Based on the idea that a layer of properly designed and manufactured fibrous material can serve as both a sound absorber and a structural damper, an approach is introduced in this article to design the microstructure of a fibrous layer for it to provide optimal damping performance. To begin with, previous work related to structural damping by fibrous layers was reviewed. Then the most appropriate models from the literature were adapted for use in the current study. A system comprising an aluminum panel and a limp fibrous layer was driven by a line force, and both the spatial velocity response of the panel and the power distribution within the system were calculated to quantify the degree of damping provided by the fibrous layer, which helped identify the airflow resistivity that provides optimal damping for any frequency and panel of interest. Given the optimal airflow resistivity, a model relating fiber microstructure to airflow resistivity was used to infer the optimal microstructure required to achieve the optimal damping performance. One finding of the current work, for example, was that as the target frequency was reduced, the fiber size required to achieve the optimal damping performance increased.

Topoisomerase 3ß is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction.

Human cells contain five topoisomerases in the nucleus and cytoplasm, but which one is the major topoisomerase for mRNAs is unclear. To date, Top3ß is the only known topoisomerase that possesses RNA topoisomerase activity, binds mRNA translation machinery and interacts with an RNA-binding protein, FMRP, to promote synapse formation; and Top3ß gene deletion has been linked to schizophrenia. Here, we show that Top3ß is also the most abundant mRNA-binding topoisomerase in cells. Top3ß, but not other topoisomerases, contains a distinctive RNA-binding domain; and deletion of this domain diminishes the amount of Top3ß that associates with mRNAs, indicating that Top3ß is specifically targeted to mRNAs by its RNA binding domain. Moreover, Top3ß mutants lacking either its RNA-binding domain or catalytic residue fail to promote synapse formation, suggesting that Top3ß requires both its mRNA-binding and catalytic activity to facilitate neurodevelopment. Notably, Top3ß proteins bearing point mutations from schizophrenia and autism individuals are defective in association with FMRP; whereas one of the mutants is also deficient in binding mRNAs, catalyzing RNA topoisomerase reaction, and promoting synapse formation. Our data suggest that Top3ß is the major topoisomerase for mRNAs, and requires both RNA binding and catalytic activity to promote neurodevelopment and prevent mental dysfunction.

RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals.

DNA Topoisomerases are essential to resolve topological problems during DNA metabolism in all species. However, the prevalence and function of RNA topoisomerases remain uncertain. Here, we show that RNA topoisomerase activity is prevalent in Type IA topoisomerases from bacteria, archaea, and eukarya. Moreover, this activity always requires the conserved Type IA core domains and the same catalytic residue used in DNA topoisomerase reaction; however, it does not absolutely require the non-conserved carboxyl-terminal domain (CTD), which is necessary for relaxation reactions of supercoiled DNA. The RNA topoisomerase activity of human Top3ß differs from that of Escherichia coli topoisomerase I in that the former but not the latter requires the CTD, indicating that topoisomerases have developed distinct mechanisms during evolution to catalyze RNA topoisomerase reactions. Notably, Top3ß proteins from several animals associate with polyribosomes, which are units of mRNA translation, whereas the Top3 homologs from E. coli and yeast lack the association. The Top3ß-polyribosome association requires TDRD3, which directly interacts with Top3ß and is present in animals but not bacteria or yeast. We propose that RNA topoisomerases arose in the early RNA world, and that they are retained through all domains of DNA-based life, where they mediate mRNA translation as part of polyribosomes in animals.

FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks.

FANCM is a highly conserved DNA remodeling enzyme that promotes the activation of the Fanconi anemia DNA repair pathway and facilitates replication traverse of DNA interstrand crosslinks. However, how FANCM interacts with the replication machinery to promote traverse remains unclear. Here, we show that FANCM and its archaeal homolog Hef from Thermoplasma acidophilum interact with proliferating cell nuclear antigen (PCNA), an essential co-factor for DNA polymerases in both replication and repair. The interaction is mediated through a conserved PIP-box; and in human FANCM, it is strongly stimulated by replication stress. A FANCM variant carrying a mutation in the PIP-box is defective in promoting replication traverse of interstrand crosslinks and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi anemia pathway. Our data reveal a conserved interaction mode between FANCM and PCNA during replication stress, and suggest that this interaction is essential for FANCM to aid replication machines to traverse DNA interstrand crosslinks prior to post-replication repair.