Research On The DNA Damage Repair Factor RCC1 In The Occurrence And Development Of Cancer

Several recent clinical studies have found abnormal expression or mutation of RCC1 in some cancer cases.RCC1,as a guanosine exchange factor of Ran,is localized in the nucleus and binds to chromatin to regulate a variety of cellular physiological pathways,such as transnuclear transport and cycle regulation.Previous studies have found that RCC1 can participate in DNA damage repair and maintain the level of histone acetylation in cells,but the specific mechanism has not been explored.Cancer is the second leading cause of death in the world.Genome instability,imbalance of histone modification and gene expression disorder are typical molecular characteristics of various cancers.Therefore,this study will focus on the effect of RCC1 on cancer formation from two perspectives of RCC1 maintaining genomic stability and regulating transcriptome level.In this study,we investigated(1)how RCC1 participates in DNA damage repair to maintain genomic stability,(2)how the abnormal status of RCC1 affects the transcriptional expression level of cancerrelated genes,(3)how histone modification is involved in the above processes,and(4)identified part of RCC1 cancer-related mutations.In this study,DNA damage was induced by a laser microirradiation system,ionizing radiation(IR)and DNA-damaging chemotherapeutic drugs.To explore how RCC1 maintains genomic stability by participating in DNA damage.Immunofluorescence was used to label protein co-location,co-IP was used to determine protein-protein interaction,Western blot was used to determine protein expression level changes,RNA-seq sequencing was used to reflect transcriptome level differences,MTT method was used to detect the toxicity of DNA damage drugs to cells.To explain how RCC1 affects tumor development through transcriptional level regulation.Transcriptome data of cancer samples from TCGA database and laboratory cell samples were analyzed using R language.The results are as follows:1.In normal cells,RCC1 inhibits degradation of CBP/ P300 and RNF20,maintains H2BK12 Ac and H2BK120ub1 levels,and ensures loose structure between chromatin nucleosomes and DNA,thus allowing normal transcription.PALB2 coordinated with RCC1 to maintain p300 stability.2.When the cell is damaged by double strand break.RCC1 participates in the homologous recombination repair pathway and works with PALB2 to stabilize HDAC2 retention at DNA damage sites to ensure the occurrence of H2BK12 Ac deacetylation events.3.High expression of RCC1 occurs in multiple cancer types,and patients with high expression of RCC1 in cancer tissues have a higher risk of death.RCC1 high expression influence transcription activation/inhibition of histone modification,promote angiogenesis,inflammation,blood clotting and acid metabolism for cancer signaling pathways in the development of protein expression of transcription,active oxygen activation pathway and Myc depend on proliferation,promote the development of primary and metastatic tumors of the formation of blood vessels in the process of the micro environment.4.5 single nucleotide mutants associated with RCC1 cancer were selected.R147 Q restricts the interaction between RCC1 and Ran.R217 Q restricts the interaction between RCC1 and PALB2.R222 Q affects the nuclear localization of RCC1.Q271 H restricts the interaction between RCC1 and Ran.E322 K affects the interaction between RCC1 and Ran and PALB2,and the localization of RCC1 in chromatin.The drug toxicity of the five mutants to DNA damage drugs was different.In conclusion,this study clarified the regulation mechanism of RCC1 on histone modification under normal physiological state and DNA damage state,and clarified that RCC1 maintains genome stability by participating in DNA damage response and regulating chromatin loose structure.It was confirmed that high expression of RCC1 can promote the development of tumor and is correlated with poor prognosis of cancer,revealing that high expression of RCC1 affects tumor-related genes and pathways at the transcriptional level.Therefore,this study reveals the mechanism of RCC1 in tumor genesis and development from two dimensions of RCC1's involvement in gene stability maintenance and transcriptional level regulation,which will provide theoretical basis for clinical diagnosis and treatment.