Biology subjects

Hou, L.

Publications and source records attributed to Hou, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Identification and characterization of a beta-1,4 Galactosidase from Elizabethkingia meningoseptica and its application on living cell surface

The biological function of terminal galactose on glycoprotein is an open field of research. Although progress had being made on enzymes that can remove the terminal galactose on glycoproteins, there is a lack of report on galactosidases that can work directly on living cells. In this study, a unique beta 1,4 galactosidase was isolated from Elizabethkingia meningoseptica (Em). It exhibited favorable stability at various temperatures (4-37) and pH (5-8) levels and can remove {beta}-1, 4 linked galactoses directly from glycoproteins. Using Alanine scanning, we found that two acidic residues (Glu-468, and Glu-531) in the predicted active pocket are critical for galactosidase activity. In addition, we also demonstrated that it could cleave galactose residues present on living cell surface. As the enzyme has a potential application for living cell glycan editing, we named it glycan editing galactosidase I or geGalaseI. In summary, our findings lay the groundwork for prospective investigations by presenting a prompt and gentle approach for the removal of galactose moieties from cell surface.

biochemistry↗

bioRxiv2023

Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

genetics↗

bioRxiv2023

Differential substrate affinity and catabolite repression enable preferential use of urea by ammonia-oxidizing bacteria

Four distinct lineages of ammonia-oxidizing microorganisms (AOM) collectively contribute to one of the largest nitrogen fluxes in the global nitrogen budget. AOM possess widely different specific affinities for ammonia, thought to determine their niche differentiation. Nevertheless, ammonia-oxidizing archaea and bacteria (AOA, AOB), and complete ammonia oxidizers (comammox) co-occur in soils, freshwater sediments, and aquifers, suggesting that other factors must drive their coexistence. Here, we show that representatives of four AOM lineages employ distinct regulatory strategies for ammonia or urea utilization, thereby minimizing direct competition for either substrate. The tested AOA and comammox species preferentially used ammonia over urea, while beta-proteobacterial AOB favored urea utilization, repressed ammonia transport in the presence of urea, and showed higher affinity for urea than ammonia, whereas gamma-proteobacterial AOB co-utilized both substrates. Stable isotope tracing, kinetics, and transcriptomics experiments revealed that both assimilation and oxidation of ammonia are transport-dependent. These results reveal novel mechanisms of nitrogen metabolism regulation and transporter-based affinity underlying the contrasting niche adaptation and coexistence patterns among the major AOM lineages.

microbiology↗

bioRxiv2023

Validation of human telomere length trans-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as novel human telomere length regulation genes

Telomere length genome-wide association studies (GWAS) have become well-powered to detect novel genes in telomere length regulation. However, no prior work has validated these putative novel genes to confirm the contribution of GWAS loci to telomere length regulation. We conducted a trans-ancestry meta-analysis of 211,369 individuals. Through enrichment analyses of chromatin state and cell-type heritability we identified blood and immune cells as the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6, a component of an E3 ubiquitin ligase complex, and POP5, a component of the Ribonuclease P/MRP complex, and demonstrating that both lengthened telomeres as predicted by our statistical analyses. CRISPR/Cas9 deletion of the predicted causal regions of these association peaks in K562 immortalized blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5, respectively. Together our results demonstrate the utility of telomere length GWAS in the identification of novel telomere length regulation mechanisms and highlight the importance of the proteasome-ubiquitin pathway in telomere length regulation.

genetics↗

bioRxiv2023

Cofea: correlation-based feature selection for single-cell chromatin accessibility data

Single-cell sequencing technologies have revolutionized the understanding of cellular heterogeneity at an unprecedented resolution. However, the high-noise and high-dimensional nature of single-cell data poses challenges for downstream analysis, and thus increases the demand for selecting biologically informative features when processing and analyzing single-cell data. Such approaches are mature for single-cell RNA sequencing (scRNA-seq) data, while for single-cell chromatin accessibility sequencing data, the epigenomic profiles at the cellular level, there is a significant gap in the availability of effective methods. Here we present Cofea, a correlation-based framework that focuses on the correlation between accessible chromatin regions, to accurately select scCAS datas features which are highly relevant to biological processes. With various simulated datasets, we quantitively demonstrate the advantages of Cofea for capturing cellular heterogeneity of imbalanced cell populations or differentiation trajectories. We further demonstrate that Cofea outperforms existing feature selection methods in facilitating downstream analysis, particularly in cell clustering, on a wide range of real scCAS datasets. Applying this method to identification of cell type-specific peaks and candidate enhancers, pathway enrichment analysis and partitioned heritability analysis, we show the potential of Cofea to uncover functional biological process and the genetic basis of cellular characteristics.

bioinformatics↗

bioRxiv2023

Mass-immigration shapes the antibiotic resistome of wastewater treatment plants

Wastewater treatment plants (WWTPs) are the hotspots for the spread of antibiotic resistance genes (ARGs) into the environment. Nevertheless, a comprehensive assessment of the city-level and short-term daily variations of ARG surveillance is still lacking in WWTPs. Here, 285 ARGs and ten mobile gene elements (MGEs) were monitored in seven WWTPs in Xiamen via high-throughput qPCR (HT-qPCR) for seven days. The average daily load of ARGs to WWTPs was about 1.21 x 1020 copies/d, and a total of 1.44 x 1018 copies/d was discharged to the environment across the entire city. Interestingly, no daily variations were observed in ARG richness, abundance, and community composition. Stochastic processes were the main force determining the assembly of ARG communities, with their relative importance ranked in the order of influent (INF) > effluent (EFF) > activated sludge (AS). Further analyses indicated that bacteria and ARGs from upstream treatment units played an increasingly dominant role in shaping ARG communities in AS and EFF, respectively, suggesting the importance of mass-immigration of bacteria and ARGs from the source on ARG transport in wastewater treatment units. This emphasizes the need to revise the way we mitigate ARG contamination but focus on the source of ARGs in urban wastewater.

microbiology↗

bioRxiv2023

Structural variation across 138,134 samples in the TOPMed consortium

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hemotologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

genomics↗

bioRxiv2022

Conventional dendritic cells 2, the targeted antigen-presenting-cell, induces enhanced type 1 immune responses in mice immunized with CVC1302 in oil formulation

Multifunctional CD4+ T helper 1 (Th1) cells, producing IFN-{gamma}, TNF- and IL-2, define a correlate of vaccine-mediated protection against intracellular infection. In our previous study, we found that CVC1302 in oil formulation promoted the differentiation of IFN-{gamma}+/TNF-+/IL-2+ Th1 cells. In order to extend the application of CVC1302 in oil formulation, this study aimed to elucidate the mechanism of action in improving the Th1 immune response. Considering the signals required for the differentiation of CD4+ T cells to Th1 cells, we detected the distribution of innate immune cells and the model antigen OVA-FITC in lymph node (LN), as well as the quantity of cytokines produced by the innate immune cells. The results of these experiments show that, cDC2 and OVA-FITC localized to inter-follicular region (IFR) of the draining lymph nodes, inflammatory monocytes localized to both IFR and T cell zone, which mainly infiltrate from the blood. In this inflammatory niche within LN, CD4+ T cells were attracted into IFR by CXCL10, secreting by inflammatory monocytes, then activated by IL-12-secreting cDC2. Above all, CVC1302 in oil formulation, on the one hand, targeted antigen and inflammatory monocyte into the LN IFN in order to attract CD4+ T cells, on the other hand, targeted cDC2 to produce IL-12 in order to promote optimal Th1 differentiation. The new finding will provide a blueprint for application of immunopotentiators in optimal formulations. ImportanceAlong with the development of veterinary immunology, immunopotentiator and delivery system were not simply mixed with antigen, more and more attentions paid on the optimal compatibility in order to induce multifunctional immune responses. As reported, LPS formulated in IFA targeted antigens to the IFR of the LN, and recruited Mo into the IFR, then attracted antigen-specific CD4+ T cells, which differentiated into Th1 cells under the IL-12 produced by DC-SIGN+ DC(1). Herein, we further found that CVC1302 formulated with Marcol 52 induced enhanced Th1 immunity. Combined with our previous finding that CVC1302 in oil formulation induced improved humoral immunity, we concluded that CVC1302 in oil formulation provided multifunctional immunity, not only higher antibody titers to prevent pathogen infection, but also cellular immunity cytokine to prevent viral shedding.

immunology↗

bioRxiv2022

Innate immune sensing of self-derived double-stranded RNA by RIG-I-MAVS-TNF-α regulates the survival and senescence fate of SARS-2-S syncytia

Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without denovosynthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF . We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy. Significance StatementIn this paper, we directly linked SARS-2-S-triggered syncytium formation with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2-expressing cells. This is important because of the persistent existence of SARS-2-S or extracellular vesicles containing SARS-2-S during the acute and post-acute stages of SARS-CoV-2 infection in human subjects. In searching for the underlying molecular mechanisms determining syncytial fate, the formation of functional MAVS aggregates dependent on RIG-I was observed at an early stage during fusion and regulated the anti-death to senescence fate of SARS-2-S syncytia through the TNF-TNFR2 axis. We also found impaired cardiac metabolism in SARS-2-S syncytia induced by condensed WNK1. Importantly, SARS-2-Spp-exacerbated heart failure could be largely rescued by WNK1 inhibitor, anti-syncytial drug or senolytic agent. Together, we suggest that rescuing metabolism dysfunction in senescent SARS-2-S syncytia should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection.

cell biology↗

bioRxiv2022

Cell division history encodes directional information of fate transitions

Single-cell RNA-sequencing (scRNA-seq) enables systematic mapping of cellular differentiation trajectories. However, inferring the cell-fate transitions under diseases or perturbations is still challenging due to the high cellular plasticity. Here, we demonstrate that monotonically expressed genes (MEGs) along cell divisions record the directions of state transitions regardless of the cellular processes. We developed a computational framework (PhyloVelo) to identify MEGs and reconstruct a novel transcriptomic velocity field by leveraging both scRNA-seq and phylogenetic information. PhyloVelo accurately recovered linear, bifurcated and convergent differentiations in simulations and C. elegans. It outperformed current approaches for delineating cellular trajectories in embryo development and tumor evolution through analysis of five CRISPR/Cas9-based lineage tracing datasets. Together, our study unveils an internal cellular clock and provides a powerful method for cellfate analysis in diverse biological contexts.

genomics↗

bioRxiv2022

Engineering of NEMO as calcium indicators with ultra-high dynamics and sensitivity

Genetically-encoded calcium indicators (GECI) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of sub-optimal peak signal-to-baseline-ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+ transients with peak SBRs ~20-fold larger than the top-of-the-range GCaMP series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared to GCaMPs, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times larger in vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+ signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.

synthetic biology↗

bioRxiv2022

Epigenome-wide meta-analysis of BMI in nine population-based cohorts: examining the utility of methylation as a biomarker of BMI

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential utility of these cytosine-phosphate-guanine (CpG) sites in predicting metabolic health. We pooled summary statistics from six trans-ethnic EWAS of BMI representing nine cohorts (n=17058), replicated these findings in the Womens Health Initiative (WHI, n=4822) and developed an epigenetic prediction score of BMI. In the pooled EWAS, 1265 CpG sites were associated with BMI (p<1E-7), and 1238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European descent and individuals of African descent. We found five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log normalized BMI in the WHI (80% training/20% testing). This model found 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides, and lower HDL-cholesterol and LDL-cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL-cholesterol and lower glucose and triglycerides. This study identified 553 previously identified and 685 novel CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.

genetics↗

bioRxiv2022

TLR4/NF-κB Signaling Contributes to the Inflammation in Ovary and Inguinal Fats of Polycystic Ovary Syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder. It has highly heterogeneous clinical manifestations which are characterized by biochemical hyperandrogenemia, obesity, insulin resistance, dyslipidemia, anovulation, and polycystic ovaries. However, the etiologies of PCOS are still unclear. Recently, studies have found that the low-grade inflammation contributed to the occurrence of PCOS, and as a critical biomarker indicated the endocrine disruptions in PCOS. ObjectiveThis study is aimed to investigate the processes and mediators of inflammation in contributing to the development of PCOS. MethodsLetrozole (LET) induced PCOS rat model was used in this study. Body weight, body temperature, inguinal fats weight, fasting glucose level, ovarian morphology, NF-{kappa}B signaling target genes in ovary, and protein expression levels of TLR4 and NF-{kappa}B in ovarian and inguinal fats were measured in rats with placebo and LET administrations for 6 and 12 weeks. ResultsPCOS rats, especially with LET intervention for 12 weeks, had higher body weight, inguinal fats weight and fasting glucose level compared to control group. The protein expression levels of TLR4 and NF-{kappa}B in cytoplasm of ovarian and inguinal fats were increased in LET-induced PCOS rats compared to control groups, while NF-{kappa}B in nucleus were reduced in PCOS rats. The expressions of ACTB, C3, CXCL3, NQO1 and SELP in ovarian were statistically different in PCOS rats induced by LET compared to control groups. ConclusionThese findings indicated that stimulating TLR4/NF-{kappa}B pathway in inguinal fats and ovary tissues contributed to the increased inflammation in LET-induced PCOS rats, which, in turn, exacerbated the phenotype of PCOS including weight gain, adipose tissue accumulation, hyperglycemia and follicular dysplasia.

pathology↗

bioRxiv2022

Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

The UK Biobank Pharma Proteomics Project (UKB-PPP) is a collaboration between the UK Biobank (UKB) and thirteen biopharmaceutical companies characterising the plasma proteomic profiles of 54,306 UKB participants. Here, we describe results from the first phase of UKB-PPP, including protein quantitative trait loci (pQTL) mapping of 1,463 proteins that identifies 10,248 primary genetic associations, of which 85% are newly discovered. We also identify independent secondary associations in 92% of cis and 29% of trans loci, expanding the catalogue of genetic instruments for downstream analyses. The study provides an updated characterisation of the genetic architecture of the plasma proteome, leveraging population-scale proteomics to provide novel, extensive insights into trans pQTLs across multiple biological domains. We highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement proteins, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug target discovery by extending the genetic proxied effect of PCSK9 levels on lipid concentrations, cardio- and cerebro-vascular diseases, and additionally disentangle specific genes and proteins perturbed at COVID-19 susceptibility loci. This public-private partnership provides the scientific community with an open-access proteomics resource of unprecedented breadth and depth to help elucidate biological mechanisms underlying genetic discoveries and accelerate the development of novel biomarkers and therapeutics.

genetics↗

bioRxiv2022

Hydrological dynamics drive the transition of antibiotic resistance genes between particle-attached and free-living lifestyles in a deep freshwater reservoir

Despite the growing awareness of antibiotic resistance genes (ARGs) spreading in the environment, there is a knowledge gap on the fate and transport of ARGs in particle-attached (PA) and free-living (FL) lifestyles in deep freshwater ecosystems experiencing seasonal hydrological changes. Here, we examined the ARG profiles using high-throughput quantitative PCR in PA and FL lifestyles at four seasons representing two hydrological seasons (i.e., vertical mixing and thermal stratification) in the Shuikou Reservoir (SR), Southern China. The results indicated that seasonal hydrological dynamics were critical for influencing ARGs in PA and FL fractions, and the transition of ARGs between the two lifestyles. Although both PA and FL ARG profiles were likely to be shaped by horizontal gene transfer, PA and FL ARGs had different responses to the changes in physico-chemicals (e.g., nutrients and dissolved oxygen) caused by seasonal hydrological dynamics. The particle-associated niche (PAN) index revealed that there were 94 non-conservative ARGs (i.e., no preferences for PA and FL), 23 conservative ARGs that preferred PA lifestyle, and 16 conservative ARGs for FL lifestyle. A sharp decline in the number of conservative ARGs in stratified seasons suggests a hydrological dynamics-dependent transition of ARGs between two lifestyles. Remarkably, the conservative ARGs (in PA or FL lifestyle) were more closely related to bacterial OTUs in their preferred lifestyle compared to their counterpart lifestyle, suggesting a lifestyle-dependent ARG enrichment. Altogether, these findings enhance our understanding of the role of seasonal hydrological changes in the dissemination of ARGs in different size fractions in deep aquatic ecosystems.

ecology↗

bioRxiv2022

Quantifying portable genetic effects and improving cross-ancestry genetic prediction with GWAS summary statistics

Polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of Europeans are known to have substantially reduced predictive accuracy in non-European populations, limiting its clinical utility and raising concerns about health disparities across ancestral populations. Here, we introduce a novel statistical framework named X-Wing to improve predictive performance in ancestrally diverse populations. X-Wing quantifies local genetic correlations for complex traits between populations, employs a novel annotation-dependent estimation procedure to amplify correlated genetic effects between populations, and combines multiple population-specific PRS into a unified score with GWAS summary statistics alone as input. Through extensive benchmarking, we demonstrate that X-Wing pinpoints portable genetic effects and substantially improves PRS performance in non-European populations, showing 18.7%-122.1% gain in predictive R2 compared to state-of-the-art methods based on GWAS summary statistics. Overall, X-Wing addresses critical limitations in existing approaches and may have broad applications in cross-population polygenic prediction.

genetics↗

bioRxiv2022

Cell detoxification of secondary metabolites by P4-ATPase mediated vesicle transport

Mechanisms for cellular detoxification of drug compounds are of significant interest in human health. Cyclosporine A (CsA) and tacrolimus (FK506) are widely known antifungal and immunosuppressive microbial natural products. However, both compounds can result in significant side effects when used as immunosuppressants. The insect pathogenic fungus Beauveria bassiana shows resistance to CsA and FK506. However, the mechanisms underlying the resistance have remained unknown. Here, we identify a P4-ATPase gene, BbCRPA, from the fungus, which confers resistance via a unique vesicle mediated transport pathway that targets the compounds into detoxifying vacuoles. Interestingly, the expression of BbCRPA in plants promotes resistance to the phytopathogenic fungus Verticillium dahliae via detoxification of the mycotoxin cinnamyl acetate using a similar pathway. Our data reveal a new function for a subclass of P4-ATPases in cell detoxification. The P4-ATPases conferred cross-species resistance can be exploited for plant disease control and human health protection.

microbiology↗

bioRxiv2022

The multi-BRCT domain protein DDRM2 is required for homologous recombination in plants

DNA double-strand breaks (DSBs) are the most toxic DNA damage for cells. Homologous recombination (HR) is a precise DSB repair mechanism as well as a basis for gene targeting using genome-editing techniques. Despite the importance of HR, the HR mechanism in plants is poorly understood. In a genetic screen for DNA Damage Response Mutants (DDRMs), we find that the Arabidopsis ddrm2 mutant is hypersensitive to DSB-inducing reagents. DDRM2 encodes a protein with four BRCA1 C-terminal (BRCT) domains and is highly conserved in plants including the earliest land plant linage, bryophytes. The plant-specific transcription factor SOG1 binds to the promoter of DDRM2 and activates its expression, suggesting that DDRM2 is a direct target of SOG1. In consistence, the expression of DDRM2 is induced by DSBs in a SOG1-dependent manner. Epistasis analysis indicates that DDRM2 functions downstream of SOG1. Similar to the sog1 mutant, the ddrm2 mutant shows dramatically reduced HR efficiency. Our study suggests that the SOG1-DDRM2 module is required for HR, providing new insights into the HR mechanisms in plants and a potential target for improving the efficiency of gene targeting. One Sentence SummaryA genetic screen in Arabidopsis reveals that the multi-BRCT domain protein DDRM2 is required for homologous recombination and is targeted by the master DNA damage response regulator SOG1.

plant biology↗