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• Research Paper Volume 13, Issue 2 pp 2365-2378

  The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses

  Relevance score: 13.962586

  Pei Zhou, Xueying Wu, Huan Chen, Ying Hu, Henghui Zhang, Lijia Wu, Ying Yang, Beibei Mao, Huaqing Wang

  Keywords: colon cancer, biomarker, homologous recombination deficiency, immunotherapy, microsatellite stable

  Published in Aging on December 9, 2020

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  Background: Microsatellite-stable (MSS) colon adenocarcinoma (COAD) patients are not sensitive to immune checkpoint inhibitors. Here, we focused on analyzing the relationship between homologous recombination repair (HRR)-related gene mutations and clinical immunotherapy responses in MSS COAD.

  Methods: The mutational landscape was profiled in a cohort of 406 Chinese COAD patients via next-generation sequencing (NGS). Correlations between HRR gene mutations and tumor immunity or clinical outcomes in two COAD genomic datasets were analyzed via bioinformatics.

  Results: In the Chinese cohort, seventy (17%) patients exhibited genomic alterations in HRR genes; ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%) were the most frequently mutated. In the MSK-IMPACT COAD cohort (immune checkpoint inhibitor-treated), HRR-mut patients (n=34) survived longer than HRR-wt patients (n=50) (log-rank P < 0.01). Based on the TCGA MSS COAD cohort, HRR gene mutations increased immune activities, such as infiltration of cytotoxic cells (P < 0.05) and exhausted CD8+ T cells (P < 0.01), and increased the IFN-γ scores (P < 0.05). The results differed in MSI-H COAD patients (all P > 0.05).

  Conclusion: HRR gene mutations significantly increased immune activities in MSS COAD patients, implying the feasibility of the HRR-mut status as an immunotherapy response predictor in MSS COAD.

• Review Volume 7, Issue 12 pp 1050-1065

  DNA repair and aging: the impact of the p53 family

  Relevance score: 11.772301

  Sara Nicolai, Antonello Rossi, Nicola Di Daniele, Gerry Melino, Margherita Annicchiarico-Petruzzelli, Giuseppe Raschellà

  Keywords: aging, DNA repair, p53, p63, p73, homologous recombination, Non homologous end joining

  Published in Aging on December 11, 2015

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  Cells are constantly exposed to endogenous and exogenous factors that threaten the integrity of their DNA. The maintenance of genome stability is of paramount importance in the prevention of both cancer and aging processes. To deal with DNA damage, cells put into operation a sophisticated and coordinated mechanism, collectively known as DNA damage response (DDR). The DDR orchestrates different cellular processes, such as DNA repair, senescence and apoptosis. Among the key factors of the DDR, the related proteins p53, p63 and p73, all belonging to the same family of transcription factors, play multiple relevant roles. Indeed, the members of this family are directly involved in the induction of cell cycle arrest that is necessary to allow the cells to repair. Alternatively, they can promote cell death in case of prolonged or irreparable DNA damage. They also take part in a more direct task by modulating the expression of core factors involved in the process of DNA repair or by directly interacting with them. In this review we will analyze the fundamental roles of the p53 family in the aging process through their multifaceted function in DDR.

  

  The accumulation of DNA damage plays a pivotal role in triggering the aging process. The progressive failure of the efficiency of the DNA repair mechanisms induces a feedback loop that enforces the aging process.

  
  
  

  

  Different damage-specific glycosylases (such as OGG1 or UNG) recognize and excise the damaged base (here shown in green). The resulting AP site is target of the endonuclease APE1 that physically creates the SSB. In the short-patch sub-pathway, only one nucleotide is replaced by Polβ while the gap is sealed by XRCC1-ligase IIIα. On the other hand, during the long-patch sub-pathway, Polδ/ε synthesize 2-8 nucleotides and FEN1 removes the 5′ flap DNA, whereas the ligation step is carried out by the complex PCNA-ligase I; NER: The initial step of lesion detection (here shown in yellow) is the only difference between GG-NER and TC-NER and it is executed by XPC/XPE or by CSB/CSA, respectively. After this step, the DNA helix is locally opened by the helicases subunits of TFIIH that allow the damage verification by XPA. The endonucleases XPF and XPG finally perform a dual incision flanking the lesion, thus releasing a 25-30 nucleotides oligomer. The single-strand gap is filled by the polymerases δ and ε, while the final nick is sealed by DNA ligase I and the complex XRCC1-ligase IIIα. (Right) DSBs repair mechanisms: HR: This process is initiated by the resection of the DSB by the nuclease activity of the MRN complex, in order to generate 3′ ssDNA tails. The protruding DNA is rapidly coated by RPA protein to keep it unwound; then Rad51, supported by several other factors such as BRCA1, BRCA2 and Rad52, drives the formation of the nucleoprotein filament on the ssDNA coated with RPA. RAD51 also mediates the strand invasion and the search for homologous sequences of the nucleoprotein complex. The process ends with the resolution of Holliday junction; NHEJ: The heterodimer Ku70/Ku86 rapidly senses the presence and binds to free dsDNA ends, thus recruiting and activating the DNA-PK catalytic subunit. The kinase activity of DNA-PK is required to activate the nuclease activity of Artemis, necessary to process ends before joining. The Ligase IV and its cofactor XRCC4 finally perform the ligation step. XLF and XLS are recently established members of this pathway whose functions are still under debate.

  
  
  

  

  Gene and protein structures of p53 (top), p63 (middle) and p73 (bottom). Colors indicate protein domains encoded by the exons. The different transcription start sites P1 and P2 (indicated by blue arrows) give rise, respectively, to the TA and ∆N isoforms in both p63 and p73. In p53 gene the existence of an alternative translation start site (shown in red) generates the ∆40 isoform, while the ∆133 is transcribed by the P2 promoter. The multiple alternative splicing events leading to the different protein isoforms are represented by black dotted lines. Black solid lines represent splicing events leading to the formation of α proteins, the longest isoforms of each family member. Splicing of consecutive exons is omitted for simplicity. TAD, transactivation domain; DBD, DNA-binding domain; OD, oligomerization domain; SAM, sterile α-motif domain; TID, transcription inhibitory domain.

  
  
  

  

  p53 family proteins are involved in different mechanisms after the induction of a DNA damage. A transient block of cell cycle progression gives time to the cells to repair the DNA. Nevertheless, p53 family proteins can also directly affect the DNA repair mechanisms (see text for details). However, if the damage is too extensive or cannot be repaired, p53 family members could trigger either a permanent exit from the cell cycle (senescence) or a cell death program (apoptosis) as mechanisms of defense. The overall result can be read as a check of the genomic stability that protects cells from aging.

  
  
  

• Research Paper pp undefined-undefined

  14-3-3σ downregulation sensitizes pancreatic cancer to carbon ions by suppressing the homologous recombination repair pathway

  Relevance score: 10.957709

  Dandan Wang, Hongtao Luo, Yanliang Chen, Yuhong Ou, Meng Dong, Junru Chen, Ruifeng Liu, Xiaohu Wang, Qiuning Zhang

  Keywords: carbon ion radiation, 14-3-3σ, pancreatic adenocarcinoma, DNA damage response, homologous recombination repair

  Published in Aging on Invalid Date

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  This study explored the role of 14-3-3σ in carbon ion-irradiated pancreatic adenocarcinoma (PAAD) cells and xenografts and clarified the underlying mechanism. The clinical significance of 14-3-3σ in patients with PAAD was explored using publicly available databases. 14-3-3σ was silenced or overexpressed and combined with carbon ions to measure cell proliferation, cell cycle, and DNA damage repair. Immunoblotting and immunofluorescence (IF) assays were used to determine the underlying mechanisms of 14-3-3σ toward carbon ion radioresistance. We used the BALB/c mice to evaluate the biological behavior of 14-3-3σ in combination with carbon ions. Bioinformatic analysis revealed that PAAD expressed higher 14-3-3σ than normal pancreatic tissues; its overexpression was related to invasive clinicopathological features and a worse prognosis. Knockdown or overexpression of 14-3-3σ demonstrated that 14-3-3σ promoted the survival of PAAD cells after carbon ion irradiation. And 14-3-3σ wad upregulated in PAAD cells during DNA damage (carbon ion irradiation, DNA damaging agent) and promotes cell recovery. We found that 14-3-3σ resulted in carbon ion radioresistance by promoting RPA2 and RAD51 accumulation in the nucleus in PAAD cells, thereby increasing homologous recombination repair (HRR) efficiency. Blocking the HR pathway consistently reduced 14-3-3σ overexpression-induced carbon ion radioresistance in PAAD cells. The enhanced radiosensitivity of 14-3-3σ depletion on carbon ion irradiation was also demonstrated in vivo. Altogether, 14-3-3σ functions in tumor progression and can be a potential target for developing biomarkers and treatment strategies for PAAD along with incorporating carbon ion irradiation.