The c-Abl-RACK1-FAK signaling axis promotes renal fibrosis in mice through regulating fibroblast-myofibroblast transition.

BACKGROUND: Renal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood. METHODS: To investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts. RESULTS: In this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis. CONCLUSIONS: Our findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.

A stromal lineage maintains crypt structure and villus homeostasis in the intestinal stem cell niche.

BACKGROUND: The nutrient-absorbing villi of small intestines are renewed and repaired by intestinal stem cells (ISCs), which reside in a well-organized crypt structure. Genetic studies have shown that Wnt molecules secreted by telocytes, Gli1+ stromal cells, and epithelial cells are required for ISC proliferation and villus homeostasis. Intestinal stromal cells are heterogeneous and single-cell profiling has divided them into telocytes/subepithelial myofibroblasts, myocytes, pericytes, trophocytes, and Pdgfralow stromal cells. Yet, the niche function of these stromal populations remains incompletely understood. RESULTS: We show here that a Twist2 stromal lineage, which constitutes the Pdgfralow stromal cell and trophocyte subpopulations, maintains the crypt structure to provide an inflammation-restricting niche for regenerating ISCs. Ablating Twist2 lineage cells or deletion of one Wntless allele in these cells disturbs the crypt structure and impairs villus homeostasis. Upon radiation, Wntless haplo-deficiency caused decreased production of anti-microbial peptides and increased inflammation, leading to defective ISC proliferation and crypt regeneration, which were partially rescued by eradication of commensal bacteria. In addition, we show that Wnts secreted by Acta2+ subpopulations also play a role in crypt regeneration but not homeostasis. CONCLUSIONS: These findings suggest that ISCs may require different niches for villus homeostasis and regeneration and that the Twist2 lineage cells may help to maintain a microbe-restricted environment to allow ISC-mediated crypt regeneration.

Foxp1 and Foxp4 Deletion Causes the Loss of Follicle Stem Cell Niche and Cyclic Hair Shedding by Inducing Inner Bulge Cell Apoptosis.

Quiescent hair follicle stem cells (HFSCs) reside in specialized bulge niche where they undergo activation and differentiation upon sensing niche-dependent signals during hair follicle (HF) homeostasis and wound repair. The underlying mechanism of HFSCs and bulge niche maintenance is poorly understood. Our previous study has reported that a transcription factor, forkhead box P1 (Foxp1), functions to maintain the quiescence of HFSCs. Here, we further discovered that forkhead box P4 (Foxp4), a close family member of Foxp1, had similar expression profiles in various components of HFs and formed a complex with Foxp1 in vitro and in vivo. The HF-specific deficiency of Foxp4 resulted in the precocious activation of HFSCs during hair cycles. In contrast to single Foxp1 or Foxp4 conditional knockout (cKO) mice, Foxp1/4 double cKO exerted an additive effect in the spectrum and severity of phenotypes in HFSC activation, hair cycling acceleration and hair loss, coupled with remarkable downregulation of fibroblast growth factor 18 (Fgf18) and bone morphogenetic protein 6 (Bmp6) expression in bulge cells. In addition, the double KO of Foxp1/4 induced the apoptosis of K6-positive (K6+) inner bulge cells, a well-established stem cell (SC) niche, thus resulting in the destruction of the bulge SC niche and recurrent hair loss. Our investigation reveals the synergistic role of Foxp1/4 in sustaining K6+ niche cells for the quiescence of HFSCs.

Berberine increases stromal production of Wnt molecules and activates Lgr5+ stem cells to promote epithelial restitution in experimental colitis.

BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by sustained inflammation and/or ulcers along the lower digestive tract, and have complications such as colorectal cancer and inflammation in other organs. The current treatments for IBDs, which affect 0.3% of the global population, mainly target immune cells and inflammatory cytokines with a success rate of less than 40%. RESULTS: Here we show that berberine, a natural plant product, is more effective than the frontline drug sulfasalazine in treating DSS (dextran sulfate sodium)-induced colitis in mice, and that berberine not only suppresses macrophage and granulocyte activation but also promotes epithelial restitution by activating Lgr5+ intestinal stem cells (ISCs). Mechanistically, berberine increases the expression of Wnt genes in resident mesenchymal stromal cells, an ISC niche, and inhibiting Wnt secretion diminishes the therapeutic effects of berberine. We further show that berberine controls the expression of many circadian rhythm genes in stromal cells, which in turn regulate the expression of Wnt molecules. CONCLUSIONS: Our findings suggest that berberine acts on the resident stromal cells and ISCs to promote epithelial repair in experimental colitis and that Wnt-ß-Catenin signaling may be a potential target for colitis treatment.

ELMO1 Deficiency Reduces Neutrophil Chemotaxis in Murine Peritonitis.

Peritoneal inflammation remains a major cause of treatment failure in patients with kidney failure who receive peritoneal dialysis. Peritoneal inflammation is characterized by an increase in neutrophil infiltration. However, the molecular mechanisms that control neutrophil recruitment in peritonitis are not fully understood. ELMO and DOCK proteins form complexes which function as guanine nucleotide exchange factors to activate the small GTPase Rac to regulate F-actin dynamics during chemotaxis. In the current study, we found that deletion of the Elmo1 gene causes defects in chemotaxis and the adhesion of neutrophils. ELMO1 plays a role in the fMLP-induced activation of Rac1 in parallel with the PI3K and mTORC2 signaling pathways. Importantly, we also reveal that peritoneal inflammation is alleviated in Elmo1 knockout mice in the mouse model of thioglycollate-induced peritonitis. Our results suggest that ELMO1 functions as an evolutionarily conserved regulator for the activation of Rac to control the chemotaxis of neutrophils both in vitro and in vivo. Our results suggest that the targeted inhibition of ELMO1 may pave the way for the design of novel anti-inflammatory therapies for peritonitis.

Long-term spatiotemporal variation and lung cancer risk of atmospheric polycyclic aromatic hydrocarbons (PAHs) in the Yangtze River Delta, China.

The Yangtze River Delta (YRD), which is the most developed region in China, suffers from atmospheric polycyclic aromatic hydrocarbons (PAH) pollution. However, the long-term spatiotemporal variation of atmospheric PAHs and the lung cancer risk caused by PAH exposure in the YRD remain unclear. Herein, we simulated the daily atmospheric concentration of benzo[a]pyrene (BaP, the most carcinogenic PAH) from 2001 to 2016 using an atmospheric transport model. During this period, the atmospheric BaP concentration showed a general trend of first increasing and then decreasing (average BaP concentration = 0.50 ± 0.12 ng/m3) and was highest in 2005 (0.72 ng/m3). Moreover, the BaP concentration in Jiangsu and Shanghai was 5.17- and 4.98-fold higher than that in Zhejiang. BaP pollution was severe in Jiangsu during the winter. The average area proportion of BaP exceeding the national standard in winter in Jiangsu was 69.09%. The population-weighted incremental lifetime cancer risk from 2001 to 2016 ranged 6.67 × 10-6-1.50 × 10-5, and the excess lung cancer cases ranged 1054-2130. Compared with 2005, excess lung cancer cases in the YRD decreased by 49.49% in 2016. Reducing BaP pollution in winter in Jiangsu is crucial for reducing lung cancer risk in the YRD.

Atmospheric benzo[a]pyrene in the Yangtze River Delta, China: pollution level and lung cancer risk in 2016 and future predictions.

The Yangtze River Delta (YRD) has undergone widespread polycyclic aromatic hydrocarbon (PAH) pollution. In this study, we simulated the spatial distribution of atmospheric benzo[a]pyrene (BaP, the most carcinogenic PAH) in the YRD in 2016 and 2030 under different emission scenarios using a 3-D atmospheric transport model and evaluated the lung cancer risks posed by BaP during the study years. The purpose of this study is to suggest targeted policy recommendations for policy-makers to mitigate BaP pollution through numerical simulation. Our results showed that the average BaP concentration in the YRD was 0.30 ng/m3 in 2016; however, a significant spatial variation was observed, with the highest BaP concentration in Shanghai (0.59 ng/m3). The population-weighted incremental lifetime lung cancer risk (PILCR) was 6.67 × 10-6 in 2016, whereas it ranged from 2.70 × 10-6 to 1.05 × 10-5 in 2030 under the five emission scenarios. A higher future population density in the YRD region could increase lung cancer risk. In all scenarios, Shanghai had the highest number of lung cancer cases (range: 208-476). The results suggest that BaP pollution could be effectively improved through the synergistic effect of reducing activity levels and improving technology. Finally, we provide specific suggested pollution control strategies (e.g., accelerating the use of clean energy in rural areas) for atmospheric BaP in the YRD.

Elevated HB-EGF expression in neural stem cells causes middle age obesity by suppressing Hypocretin/Orexin expression.

Obesity is common in the middle aged population and it increases the risks of diabetes, cardiovascular diseases, certain cancers, and dementia. Yet, its etiology remains incompletely understood. Here, we show that ectopic expression of HB-EGF, an important regulator of neurogenesis, in Nestin+ neuroepithelial progenitors with the Cre-LoxP system leads to development of spontaneous middle age obesity in male mice accompanied by hyperglycemia and insulin resistance. The Nestin-HB-EGF mice show decreases in food uptake, energy expenditure, and physical activity, suggesting that reduced energy expenditure underlies the pathogenesis of this obesity model. However, HB-EGF expression in appetite-controlling POMC or AgRP neurons or adipocytes fails to induce obesity. Mechanistically, HB-EGF suppresses expression of Hypocretin/Orexin, an orexigenic neuropeptide hormone, in the hypothalamus of middle aged Nestin-HB-EGF mice. Hypothalamus Orexin administration alleviates the obese and hyperglycemic phenotypes in Nestin-HB-EGF mice. This study uncovers an important role for HB-EGF in regulating Orexin expression and energy expenditure and establishes a midlife obesity model whose pathogenesis involves age-dependent changes in hypothalamus neurons.

Efficient Atmospheric Transport of Microplastics over Asia and Adjacent Oceans.

We developed a regional atmospheric transport model for microplastics (MPs, 10 µm to 5 mm in size) over Asia and the adjacent Pacific and Indian oceans, accounting for MPs' size- and shape-dependent aerodynamics. The model was driven by tuned atmospheric emissions of MPs from the land and the ocean, and the simulations were evaluated against coastal (n = 19) and marine (n = 56) observations. Our tuned atmospheric emissions of MPs from Asia and the adjacent oceans were 310 Gg y-1 (1 Gg = 1 kton) and 60 Gg y-1, respectively. MP lines and fragments may be transported in the atmosphere >1000 km; MP pellets in our model mostly deposited near-source. We estimated that 1.4% of the MP mass emitted into the Asian atmosphere deposited into the oceans via atmospheric transport; the rest deposited over land. The resulting net atmospheric transported MP flux from Asia into the oceans was 3.9 Gg y-1, twice as large as a previous estimate for the riverine-transported MP flux from Asia into the oceans. The uncertainty of our simulated atmospheric MP budget was between factors of 3 and 7. Our work highlighted the impacts of the size and morphology on the aerodynamics of MPs and the importance of atmospheric transport in the source-to-sink relationship of global MP pollution.

The noncanonical BMP signaling pathway plays an important role in club cell regeneration.

The bronchiole is a major site for the development of several life-threatening disorders, including chronic obstructive pulmonary disease and lung adenocarcinomas. The bronchiolar epithelium is composed of club cells and ciliated epithelial cells, with club cells serving as progenitor cells. Presently, the identity of the cells involved in regeneration of bronchiolar epithelium and the underlying mechanisms remain incompletely understood. Here, we show that Prrx1, a homeobox transcription factor, can mark club cells in adult mice during homeostasis and regeneration. We further show that the noncanonical signaling pathway of BMPs, BMPR1A-Tak1-p38MAPK, plays a critical role in club cell regeneration. Ablation of Bmpr1a, Tak1, or Mapk14 (encoding p38α) in Prrx1+ club cells caused minimal effect on bronchiolar epithelium homeostasis, yet it resulted in severe defects in club cell regeneration and bronchiole repair in adult mice. We further show that this pathway supports proliferation and expansion of the regenerating club cells. Our findings thus identify a marker for club cells and reveal a critical role for the BMP noncanonical pathway in club cell regeneration.

Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion.

Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.

LRRK2 interacts with ATM and regulates Mdm2-p53 cell proliferation axis in response to genotoxic stress.

Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin. We found that DNA damage enhances LRRK2 phosphorylation at Serine 910, Serine 935 and Serine 1292. We further showed that LRRK2 phosphorylation is abolished in the absence of ATM, suggesting that LRRK2 phosphorylation requires ATM. It should also be noted that LRRK2 interacts with ATM. In contrast, overexpression or knockdown of LRRK2 does not affect ATM phosphorylation, indicating that LRRK2 is the downstream target of ATM in response to DNA damage. Moreover, we demonstrated that LRRK2 increases the expression of p53 and p21 by increasing the Mdm2 phosphorylation in response to DNA damage. Loss-of-function in LRRK2 has the opposite effect to that of LRRK2. In addition, FACS analysis revealed that LRRK2 enhances cell cycle progression into S phase in response to DNA damage, a finding that was confirmed by 5-bromo-2'-deoxyuridine immunostaining. Taken together, our findings demonstrate that LRRK2 plays an important role in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage.

New Method for Improving Spatial Allocation Accuracy of Industrial Energy Consumption and Implications for Polycyclic Aromatic Hydrocarbon Emissions in China.

The variety of spatial allocation methods for industrial sources can significantly affect the distribution of a gridded pollutant emission inventory. Although uncertainties in current emissions inventories have been discussed extensively, uncertainties resulting from improper spatial proxies have rarely been evaluated. Here, a new subnational fuel data disaggregation method using points-of-interest (POI) data (DPOI) for industrial sources was developed. We compared the accuracies of DPOI and six other spatial allocation methods at the city scale and within the city and found that DPOI had the highest accuracy. Using a population proxy may over-estimate the industrial energy consumption in urban centers or other densely populated areas. We further applied the DPOI to establish a 0.05° × 0.05° gridded industrial polycyclic aromatic hydrocarbon (PAH) emissions inventory in 2016. There are obvious spatial differences in industrial PAH emissions, and high industrial PAH emissions are mainly concentrated in North China and East China. Although some limitations exist, we believe that POI data and the DPOI method have great potential in the field of gridded pollutant emissions inventories and that they can further reduce the spatial allocation uncertainty of gridded emissions inventories.

Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy.

Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development. Aph2(-/-) embryos and pups showed cardiomyopathy and cardiac defects including bradycardia. We identified phospholamban, a protein often associated with human cardiomyopathy, as an interacting partner and a substrate of Aph2. Aph2-mediated palmitoylation of phospholamban on cysteine 36 differentially alters its interaction with PKA and protein phosphatase 1 α, augmenting serine 16 phosphorylation, and regulates phospholamban pentamer formation. Aph2 deficiency results in phospholamban hypophosphorylation, a hyperinhibitory form. Ablation of phospholamban in Aph2(-/-) mice histologically and functionally alleviated the heart defects. These findings establish Aph2 as a critical in vivo regulator of cardiac function and reveal roles for protein palmitoylation in the development of other organs including eyes.

Spatiotemporal distribution and dynamic modeling of atmospheric gaseous polycyclic aromatic hydrocarbons in a rapidly urbanizing city: Nanjing, China.

Multiple studies have evaluated the concentration and lung cancer risk of polycyclic aromatic hydrocarbons (PAHs). However, the monitoring and dynamic modeling of PAHs with a high resolution were relatively insufficient. We investigated the spatiotemporal distribution of gaseous PAH concentrations using passive air samplers with high sampling density in an industrial city of Nanjing, China (January and October 2015) and found that the gaseous PAH concentrations in western Nanjing were higher than those in eastern Nanjing, mainly because of emission source distribution and wind action. There were notable seasonal changes in PAH concentrations: winter > autumn > spring > summer. We developed an atmospheric PAH dynamic model with a high resolution of 1 km2 based on the advection-diffusion equation and coupled with an emissions inventory and atmospheric transportation processes. Acenaphthene was selected as a proxy for gaseous PAHs. The modeled acenaphthene concentrations were similar to the concentrations measured. Moreover, we used the model to identify the impact of meteorological factors on gaseous PAHs via scenario analysis and found that a narrow-range temperature change and even heavy rainfall may not significantly affect atmospheric gaseous PAH concentrations, whereas the wind played an important part in transferring PAHs and changing their geographic distribution.

The effects of different intensities of exercise and active vitamin D on mouse bone mass and bone strength.

Physical exercise is beneficial to bone health. However, little is known how different intensities of exercise affect bone mass and strength. In the present study, we used young mice to study the effects of different intensities of exercise on bone mass and bone strength in comparison to pharmacological doses of active vitamin D (calcitriol). We found that only the medium level of exercise tested showed a positive effect on bone mineral density, trabecular bone volume, and bone strength, which are attributable to a decrease in bone resorption and an increase in bone formation, with the latter being accompanied by an increase in the number of osteogenic mesenchymal stem cells in the bone marrow. Calcitriol increases bone volume and bone strength, yet the combination of calcitriol and medium-intensity exercise did not further improve bone mass or strength. Moreover, calcitriol also showed some protective effect on the bone in mice with high levels of exercise. These results indicate that exercise at medium intensity increases bone mass and strength via affecting both bone formation and resorption and that its beneficial effects on bone mass cannot be further improved by calcitriol.

Surface water polycyclic aromatic hydrocarbons (PAH) in urban areas of Nanjing, China.

The concentration, sources and environmental risks of polycyclic aromatic hydrocarbons (PAHs) in surface water in urban areas of Nanjing were investigated. The range of ∑16PAHs concentration is between 4,076 and 29,455 ng/L, with a mean of 17,212 ng/L. The composition of PAHs indicated that 2- and 3-ring PAHs have the highest proportion in all PAHs, while the 5- and 6-ring PAHs were the least in proportion. By diagnostic ratio analysis, combustion and petroleum were a mixture input that contributed to the water PAH in urban areas of Nanjing. Positive matrix factorization quantitatively identified four factors, including coke oven, coal combustion, oil source, and vehicle emission, as the main sources. Toxic equivalency factors of BaP (BaPeq) evaluate the environmental risks of PAHs and indicate the PAH concentration in surface water in urban areas of Nanjing had been polluted and might cause potential environmental risks. Therefore, the PAH contamination in surface water in urban areas of Nanjing should draw considerable attention.

Foxp1/2/4 regulate endochondral ossification as a suppresser complex.

Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification.

A potential role for protein palmitoylation and zDHHC16 in DNA damage response.

BACKGROUND: Cells respond to DNA damage by activating the phosphatidylinositol-3 kinase-related kinases, p53 and other pathways to promote cell cycle arrest, apoptosis, and/or DNA repair. Here we report that protein palmitoylation, a modification carried out by protein acyltransferases with zinc-finger and Asp-His-His-Cys domains (zDHHC), is required for proper DNA damage responses. RESULTS: Inhibition of protein palmitoylation compromised DNA damage-induced activation of Atm, induction and activation of p53, cell cycle arrest at G2/M phase, and DNA damage foci assembly/disassembly in primary mouse embryonic fibroblasts. Furthermore, knockout of zDHHC16, a palmitoyltransferase gene identified as an interacting protein for c-Abl, a non-receptor tyrosine kinase involved in DNA damage response, reproduced most of the defects in DNA damage responses produced by the inhibition of protein palmitoylation. CONCLUSIONS: Our results revealed critical roles for protein palmitoylation and palmitoyltransferase zDHHC16 in early stages of DNA damage responses and in the regulation of Atm activation.

An unconventional role of BMP-Smad1 signaling in DNA damage response: a mechanism for tumor suppression.

The genome is under constant attack by self-produced reactive oxygen species and genotoxic reagents in the environment. Cells have evolved a DNA damage response (DDR) system to sense DNA damage, to halt cell cycle progression and repair the lesions, or to induce apoptosis if encountering irreparable damage. The best studied DDR pathways are the PIKK-p53 and PIKK-Chk1/2. Mutations in these genes encoding DDR molecules usually lead to genome instability and tumorigenesis. It is worth noting that there exist unconventional pathways that facilitate the canonical pathways or take over in the absence of the canonical pathways in DDR. This review will summarize on several unconventional pathways that participate in DDR with an emphasis on the BMP-Smad1 pathway, a known regulator of mouse development and bone remodeling.