The DNA damage repair complex MoMMS21-MoSMC5 is required for infection-related development and pathogenicity of Magnaporthe oryzae

The conserved DNA damage repair complex,MMS21-SMC5/6(Methyl methane sulfonate 21-Structural maintenance of chromosomes 5/6),has been extensively studied in yeast,animals,and plants.However,its role in phytopathogenic fungi,particularly in the highly destructive rice blast fungus Magnaporthe oryzae,remains unknown.In this study,we functionally characterized the homologues of this complex,MoMMS21 and MoSMC5,in M.oryzae.We first demonstrated the importance of DNA damage repair in M.oryzae by showing that the DNA damage inducer phleomycin inhibited vegetative growth,infection-related development and pathogenicity in this fungus.Additionally,we discovered that MoMMS21 and MoSMC5 interacted in the nuclei,suggesting that they also function as a complex in M.oryzae.Gene deletion experiments revealed that both MoMMS21 and MoSMC5 are required for infection-related development and pathogenicity in M.oryzae,while only MoMMS21 deletion affected growth and sensitivity to phleomycin,indicating its specific involvement in DNA damage repair.Overall,our results provide insights into the roles of MoMMS21 and MoSMC5 in M.oryzae,highlighting their functions beyond DNA damage repair.

LncRNA HOTAIR promotes DNA damage repair and radioresistance by targeting ATR in colorectal cancer

Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance development.Moreover,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal cancer(CRC)progression.The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells,as well as the underlying mechanism.The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues,as well as in radiosensitive and radioresistant samples.The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test.Functional assays such as cell proliferation,colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation.RNA pull-down assay andfluorescence in situ hybridization(FISH)were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated-and Rad3-related(ATR).HOTAIR was significantly upregulated in CRC tumor tissues,especially in radioresistant tumor samples.The elevated expression of HOTAIR was correlated with more advanced histological grades,distance metastasis and the poor prognosis in patients with CRC.Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells.HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model.Moreover,the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway.Silencing HOTAIR impaired the ATR-ATR interacting protein(ATRIP)complex and signaling in cell cycle progression.Collectively,the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.

Development of a prognostic signature for esophageal cancer based on a novel 7-DNA damage repair genes signature

Esophageal cancer(EC)was an aggressive malignant neoplasm characterized by high morbidity and poor prognosis.Identifying the changes in DNA damage repair genes helps to better understand the mechanisms of carcinoma progression.In this study,by comparing EC samples and normal samples,we found a total of 132 DDR expression with a significant difference.Moreover,we revealed higher expression of POLN,PALB2,ATM,PER1,TOP3B and lower expression of HMGB1,UBE2B were correlated to longer OS in EC.In addition,a prognostic risk score based on 7 DDR gene expression(POLN,HMGB1,TOP3B,PER1,UBE2B,ATM,PALB2)was constructed for the prognosis of EC.Meanwhile,EC cancer samples were divided into 3 subtypes based on 132 DDR genes expressions.Clinical profile analysis showed cluster C1 and C2 showed a similar frequency of T2,which was remarked higher than that in cluster 3.Moreover,we found the immune cell inflation levels were significantly changed in different subtypes of EC.The infiltration levels of T cell CD8+,B cell and NK cells were greatly higher in cluster 2 than that in cluster 1 and cluster 3.The results showed T cell CD4+infiltration levels were dramatically higher in cluster 1 than that in cluster 2 and cluster 3.Finally,we perform bioinformatics analysis of DEGs among 3 subtypes of EC and found DDR genes may be related to multiple signaling,such as Base excision repair,Cell cycle,Hedgehog signaling pathway,and Glycolysis/Gluconeogenesis.These results showed DDR genes may serve as new target for the prognosis of EC and prediction of the potential response of immune therapy in EC.

Effects of β-Glucan Supplementation on Repairing of Phenol-Induced Vaginal Mucosal Epithelium Damage in Rats

Objective: To investigate the effects of different concentrations of β-glucan on the repair of damaged vaginal mucosa, the expression of vascular endothelial growth factor (VEGF), and the inflammatory factor-6 (IL-6) in vaginal tissues. Methods: Thirty-six adult female specific pathogen free (SPF)-grade Wistar rats were randomly divided into 3 phase groups with 12 rats each. Vaginal inflammation rat models were established by injecting phenol gel into the vagina of each rat at a dose of 0.1 ml/100g body weight. After modeling, rats were divided into 4 groups based on different concentrations of the test agent. The control group was injected with 0.5 ml of saline, experimental group A was injected with 0.375 ml saline 0.125 ml β-glucan, experimental group B was injected with 0.25 ml saline 0.25 ml β-glucan, and experimental group C was injected with 0.50 ml β-glucan. The injection sites were selected at the 3 o’clock and 9 o’clock positions of the vagina. Rats were sacrificed at 7-, 14-, and 28-days post-injection, and tissue samples were collected from the injection sites and prepared for histological analysis. New blood vessels and fibroblast numbers in the tissues were observed after Hematoxylin-eosin (HE) staining. The expression levels of VEGF and IL-6 in the tissues were measured using quantificational reverse transcription polymerase chain reaction (qRT-PCR). Results: Histological examination of vaginal tissue specimens at 7-, 14-, and 28-days post-injection showed that on day 7, there were no significant changes in the experimental groups compared to the control group. However, on days 14 and 28, the experimental groups showed more new blood vessels, macrophages, and fibroblasts with increased activity compared to the control group. The expression levels of VEGF in vaginal tissues were elevated on days 14 and 28 in the experimental groups. The comparison of IL-6 levels in vaginal tissues on day 28 showed that serum IL-6 levels returned to normal, and there was no statistically significant difference between the experimental and control groups. Conclusion: In the 3 experimental phases, the increase in VEGF levels in vaginal tissues on day 14 post-injection was more pronounced with higher concentrations of β-glucan, and IL-6 levels returned to normal on day 28. β-Glucan can enhance VEGF levels in damaged vaginal tissues, promote the repair of damaged vaginal tissues, and higher concentrations of β-glucan have a better effect.

Effects of SWI/SNF complex on DNA damage repair in heterochromatin of embryonic fibroblast cells

Objective:To investigate the impact of SWI/SNF complex on heterochromatin DNA damage repair after exposure to X-ray irradiation,in order to explore the underlying mechanism.Methods:NIH3T3 and MRC5 cells were treated with 50 nmol/L siRNA targeting SWI/SNF complex subunits(BRM,ARID1A,BRG1 and SNF5),and YAP/TAZ.At 24 h after transfection,the cells were irradiated with 0.5 and 1 Gy of X-rays.At 20,60 and 240 min post-irradiation,γH2AX assay was performed to evaluate the radiation response in total or heterochromatin.Comet assay was used to determine the role of YAP/TAZ in DNA damage when the cells were irradiated with 4 Gy of X-rays.NIH3T3 were treated with 50 nmol/L siRNA targeting BRM/BRG1 and YAP/TAZ to determine their relationship on heterochromatin DNA damage repair.Results:In NIH3T3,SWI/SNF complex subunits(BRM,ARID1A and BRG1)knock-down increasedγH2AX in total and heterochromatin at 1 Gy 60 min post-irradiation(P<0.05),while SNF5 knock-down decreased heterochromatinγH2AX at 1 Gy 20 min post-irradiation(P<0.05).In MRC5,BRM and BRG1 knock-down increasedγH2AX in total and heterochromatin at 1 Gy 60 min post-irradiation(P<0.05).Inconsistently,ARID1A knockdown did not affect it,and SNF5 knock-down increased heterochromatinγH2AX at 1 Gy 60 min post-irradiation(P<0.05).Moreover,YAP/TAZ knock-down decreased heterochromatinγH2AX in NIH3T3 and MRC5(P<0.05).Meanwhile,YAP/TAZ knock-down decreased Tail Moment in comet assay at 4 Gy 60 min post-irradiation(P<0.05).BRM/BRG1 combining with YAP/TAZ knock-down significantly decreased heterochromatinγH2AX compared with single BRM/BRG1 knock-down at 0.5 Gy 60 min post-irradiation(P<0.05).Conclusions:The SWI/SNF complex subunits exhibited varying effects on DNA damage repair.BRM/BRG1 knockdown promotedγH2AX accumulation in heterochromatin through YAP/TAZ.This study provides a novel direction for DNA damage repair and sheds light on the role of SWI/SNF complex in response to DNA damage repair in heterochromatin.

MRN complex is an essential effector of DNA damage repair

Genome stability can be threatened by both endogenous and exogenous agents.Organisms have evolved numerous mechanisms to repair DNA damage,including homologous recombination(HR)and non-homologous end joining(NHEJ).Among the factors associated with DNA repair,the MRE11-RAD50-NBS1(MRN)complex(MRE11-RAD50-XRS2 in Saccharomyces cerevisiae)plays important roles not only in DNA damage recognition and signaling but also in subsequent HR or NHEJ repair.Upon detecting DNA damage,the MRN complex activates signaling molecules,such as the protein kinase ataxia-telangiectasia mutated(ATM),to trigger a broad DNA damage response,including cell cycle arrest.The nuclease activity of the MRN complex is responsible for DNA end resection,which guides DNA repair to HR in the presence of sister chromatids.The MRN complex is also involved in NHEJ,and has a species-specific role in hairpin repair.This review focuses on the structure of the MRN complex and its function in DNA damage repair.

Protective role of electrophile-reactive glutathione for DNA damage repair inhibitory effect of dibromoacetonitrile

Dibromoacetonitrile(DBAN) is a disinfection byproduct(DBP) and linked with cancer in rodents, but the mechanism of its carcinogenicity has not been fully elucidated. We recently reported that DBAN induced inhibition of nucleotide excision repair(NER). In this study, we investigated if glutathione(GSH) is involved in the DBAN-induced inhibition of NER. Human keratinocytes Ha Ca T were pretreated with L-buthionine-(S,R)-sulfoximine(BSO) to deplete intracellular GSH. BSO treatment markedly potentiated the DBAN-induced NER inhibition as well as intracellular oxidation. The recruitment of NER proteins(transcription factor IIH, and xeroderma pigmentosum complementation group G) to DNA damage sites was inhibited by DBAN, which was further exacerbated by BSO treatment. Our results suggest that intracellular GSH protects cells from DBAN-induced genotoxicity including inhibition of DNA damage repair.

ADP-ribosylhydrolases:from DNA damage repair to COVID-19

Adenosine diphosphate(ADP)-ribosylation is a unique post-translational modification that regulates many biological processes,such as DNA damage repair.During DNA repair,ADP-ribosylation needs to be reversed by ADP-ribosylhydrolases.A group of ADP-ribosylhydrolases have a catalytic domain,namely the macrodomain,which is conserved in evolution from prokaryotes to humans.Not all macrodomains remove ADP-ribosylation.One set of macrodomains loses enzymatic activity and only binds to ADP-ribose(ADPR).Here,we summarize the biological functions of these macrodomains in DNA damage repair and compare the structure of enzymatically active and inactive macrodomains.Moreover,small molecular inhibitors have been developed that target macrodomains to suppress DNA damage repair and tumor growth.Macrodomain proteins are also expressed in pathogens,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).However,these domains may not be directly involved in DNA damage repair in the hosts or pathogens.Instead,they play key roles in pathogen replication.Thus,by targeting macrodomains it may be possible to treat pathogen-induced diseases,such as coronavirus disease 2019(COVID-19).

Numerical simulation of the modulation to incident laser by the repaired damage site in a fused silica subsurface

One of the main factors of laser induced damage is the modulation to incident laser which is caused by the defect in the subsurface of the fused silica. In this work, the repaired damage site irradiated by CO2 laser is simplified to a Gaussian rotation according to the corresponding experimental results. Then, the three-dimensional finite-difference time-domain method is employed to simulate the electric field intensity distribution in the vicinity of this kind of defect in fused silica front subsurface. The simulated results show that the modulation is notable, the Emax is about 2.6 times the irradiated electric field intensity in the fused silica with the damage site （the width is 1.5 μm and depth is 2.3 μm） though the damage site is repaired by CO2 laser. The phenomenon and the theoretical result of the annular laser enhancement existed on the rear surface are first verified effectively, which agrees well with the corresponding experimental results. The relations between the maximal electric field intensity in fused silica with defect depth and width are given respectively. Meanwhile, the corresponding physical mechanism is analysed theoretically in detail.

Dynamic Changes in DNA Damage and Repair Biomarkers with Employment Length among Nickel Smelting Workers

Our study explored the dynamic changes in andthe relationship between the DNA damage marker8-hydroxy-2＇-deoxyguanosine （8-OHdG） and theDNA repair marker 8-hydroxyguanine DNAglycosidase 1 （hOGG1） according to the length ofoccupational employment in nickel smeltingworkers. One hundred forty nickel-exposedsmelting workers and 140 age-matched unexposedoffice workers were selected from the Jinchangcohort. The 8-OHdG levels in smelting workers wassignificantly higher than in office workers （Z=-8.688,P〈0.05） and the 8-OHdG levels among nickelsmelting workers in the 10-14 y employment lengthcategory was significantly higher than among allpeers. The hOGG1 levels among smelting workerswere significantly lower than those of non-exposedworkers （Z=-8.948, P〈0.05）. There were significantdifferences between employment length andhOGG1 levels, with subjects employed in nickelsmelting for 10-14 y showing the highest levels ofhOGG1. Correlation analysis showed positivecorrelations between 8-OHdG and hOGG1 levels（r=0.413; P〈0.01）. DNA damage was increased withemployment length among nickel smelting workersand was related to the inhibition of hOGG1 repaircapacity.

Two types of auditory glutamatergic synapses and their implications for repairing damaged central auditory pathways

For the mammalian brain to process and decipher the rich panoply of sounds that abound in the world, nature has evolved an elegant collection of neural circuits dedicated to this task. Indeed, the complexity, variety and number of neural pathways devoted to computing auditory information is unique among sensory modalities （Kaas, 2008）. After the initial sensorineural encoding of sound at the level of the cochlea, auditory information is processed in several lower brainstem centers and eventually converges in the midbrain, at the level of the inferior colliculus （Wenstrup, 2005）, Subsequently, auditory information is transferred through the thalamus, the medial geniculate body, and then the auditory cortex （Winer et al., 2005; Razak and Fuzessery, 2010; Hackett, 2011; Lee and Sherman, 2011; Lee and Winer, 2011;

STUDY ON THE REPAIR OF DAMAGED CONCRETE WITH MMA OF SULFUR IMPREGNATION

This paper deals with the repair of damaged, plain concrete and polymer cement concrete by impregnation with methyl methacrylate (MMA) or sulfur. The stress-strain (σ-ε) curves of the unaxial compression of the concrete before and after repairing were given. The results indicate that the strength of damaged concrete can be reinstated and even improved after the concrete is impregnated with MMA or sulfur. The main mechanism of repairing is that the cracks, the original pores and microcracks are filled with MMA or sulfur, and the im-pregnant plays role in adhesion enhancement and reinforcement.

Design and Verification of Selected Technological Procedures for the Repairs of Land Vehicles Combat Damage

The paper deals with temporary repairs. Applying a different technology, using a reproduction part, or performing a repair by a serviceman without the competence is typical features of temporary repairs. Temporary repair makes possible for an object to fulfil its function for a limited time, until regular repairs can be made. The complexity perplex modern vehicles their reparability. It is necessary to look for the new procedures of the implementation so-called temporary repairs. The authors suggested procedure battle damage assessment and repair, which they expressed in the form of diagrams. There is also description of new technological procedures, which could be possibly applied in field of temporary repairs. These new procedures are applied on land (wheeled and tracked) vehicles parts and their sufficiency for Czech Army conditions is tested. The main purpose of the thesis is defining operating procedures of the most useful methods, including their verifications and proposal of tools needed for repairs. These tools should be included in equipment of vehicles operated in Czech Army. The thesis is primarily focused on repairs of mechanical parts and units and also of reparation of fuel, hydraulic and high pressure systems.

DNA plasticity and damage in amyotrophic lateral sclerosis

The pathophysiology of amyotrophic lateral sclerosis （ALS） is particularly challenging due to the heteroge- neity of its clinical presentation and the diversity of cellular, molecular and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic dis- ease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autono- mous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood. This mini review summarizes current knowledge on DNA alterations and counteracting DNA repair strategies in ALS pathology and discusses the putative role of unconventional DNA entities including transposable elements and extrachromosomal circular DNA in the disease process. Focus is set on SODl-related pathophysiology, with extension to FUS, TDP-43 and C90RF72 mutations. Advancing our knowledge in the field will contribute to an improved understanding of this relentless dis- ease, for which therapeutic options others than symptomatic approaches are almost unavailable.

The DNA damage and regulatory strategy in hematopoietic stem cells after irradiation exposure:Progress and challenges

The hematopoietic system is susceptible to ionizing radiation(IR),which can cause acute hematopoietic failure or long-term myelosuppression.As the most primitive cells of the hematopoietic hierarchy,hematopoietic stem cells(HSCs)maintain lifelong hematopoietic homeostasis and promote hematopoietic regeneration during stress.Numerous studies have shown that nuclear and mitochondrial genomes are the main targets of radiation injury in HSCs.More importantly,the damage of DNA may trigger a series of biological responses that largely determine HSC fate following IR exposure.Although some essential pathways and factors involved in DNA injury and damage in HSCs have been revealed,a comprehensive understanding of the biological effects of radiation on HSCs still needs to be improved.This review focuses on recent insights into the molecular mechanisms underlying DNA damage and repair in HSCs after IR.Then summarize corresponding regulatory measures,which may provide a reference for further research in this field.

Proteomic Alterations in Human Dermal Fibroblasts under Photo-Induced Pollution Caused by Excessive Solar Irradiations such as Infra-Red, Blue Light, UVA and UVB

Background: The skin serves as the first line of defense for the human body. Direct sunlight contains damaging radiations that can speed up the ageing process of the skin, resulting in wrinkles, leathery skin, dark patches, and solar elastosis. Objectives: To evaluate the effect of multiple solar irradiation related factors at the protein level in human dermal fibroblast (HDF). The overall effect of individual solar irradiations such as Infrared A (IRA), blue light (BL), UVA, and UVB on HDF cells and the extent of molecular level aberrations to be assessed and compared against each. Methods: Label-free quantitative proteomics (MS/MS) approach has been adopted in this study to observe the protein level changes induced in the HDF cells through various exposures of full light sources. Following that, downstream insilico analysis has been carried out. Results: In this study, it is demonstrated all the four different solar irradiations significantly contribute to the molecular degeneration of skin cells through various mechanisms. This study confirms that BL down-regulates DNA repair proteins and the skin cells-HDF stimulate the histone proteins as a response mechanism to maintain the chromosomal integrity. Conclusions: The proteomics experiment carried out in the current study intends to support the future sun care products based on full light protection technology that can be custom designed to provide complete protection from the solar radiation. Similar technology could enhance the further investigations for deeper understanding of induction, mode of action, and prevention of skin damage from extensive solar irradiation.

Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer

Since androgen receptor(AR)signaling is critically required for the development of prostate cancer(PCa),targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa.Unfortunately,although the tumor initially responds to the therapy,treatment resistance eventually develops and the disease will progress.It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling.Recent advances in pathology,molecular biology,genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression.They include neuroendocrine differentiation,cell metabolism,DNA damage repair pathways and immune-mediated mechanisms.The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families

Objective:Approximately 5%–10%of breast cancer(BC)patients display familial traits that are genetically inherited among the members of a family.The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families.Methods:Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.Results:Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8%(96/116)of the cases.Among these,80.8%of the mutated genes were related to DNA damage repair.Fourteen possible disease-causing variants were identified in 13 of 27 BC families.Only 25.9%(7/27)of the BC families exhibited hereditary deficiency in BRCA1/2 genes,while 22.2%of the BC families exhibited defects in non-BRCA genes.In all,41.7%(40/96)of the mutation carriers had BRCA mutations,88.5%(85/96)had non-BRCA mutations,and 30.2%(29/96)had both BRCA and non-BRCA mutations.The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations(P<0.05).However,the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations(P<0.05).Conclusions:In addition to BRCA1/2,genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC.Therefore,profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

Research on Penetration Rules of LY-12cz Thin Sheet Subjected to Rod-Shaped Fragment

By establishing the finite element models and corresponding calculation methods for the target board and rod-shaped fragment, the penetration effect of the high-velocity rod-shaped fragments＇ impact on the LY- 12cz thin sheet is analyzed by analog calculation. The variation rules of the residual velocity and residual mass of fragments, chock mass and crevasse shape are obtained when the fragment penetrates target board with different incidence velocities and attack angles. Corresponding fitting computation formulas are concluded from the above calculating data. The conclusions are helpful to analyzing the destructivity of fragment and protective ability of aircraft structure. In addition, they can guide the research for battle damage mode and assessment effectively.

Mitotic Slippage Process Concealed Cancer-Sought Chromosome Instability Mechanism (S-CIN)

Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer initiation, and on the question of a mechanism for inherited CIN (chromosomal instability). Evidence for fitness increased cells from the mitotic slippage process (in vivo/in vitro) originated from genome damaged diploid cells in G2/M, skipping mitosis to G1, which illegitimately permitted S-phase re-replication of the chromatid cohesed-2n cells to 4n-tetraploidy. During which, down-load of genome-wide cohesin occurred, producing 4-chromatid diplochromosomes, evolutionary conserved in repair of DNA. This type of 4n cells divided 2-step meiotic-like, leading to diploid aneuploid cells with increased fitness, and expression of gross chromosomal anomalies in proliferation. The diploid cohesed chromatids during re-replication would hinder replication of sticky heterochromatic regions, resulting in their under-replication, and known from Drosophila. The human chromosomes are longitudinally differentiated into satellite DNA regions, folic acid sensitive sites and the primary constriction (centromere);they are breakage sensitive regions and being heterochromatic. This strongly suggests, multiple, chromosomal regional under-replication-cites, translated to origin of slippage, S-CIN, a genome inherited destabilization mechanism. Logically, S-CIN would affect genes differentially depending on chromosome location, for example, the high frequency in cancers of mutated p53 on the small 17p-arm, which with centromere breakage would be preferentially lost in mitosis. This likely S-CIN mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process.