DNA Damage Response and Immune Defense

Nastasi, Claudia; Mannarino, Laura; D’Incalci, Maurizio

doi:10.3390/ijms21207504

Cited by 87 publications

(56 citation statements)

References 199 publications

(221 reference statements)

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“…Consistent with previous reports BRCA mutations in breast cancer were mostly associated with regulation of cell cycle, DNA damage, and cell proliferation in breast cancer [ 71 ], and with immune system-related processes in ovarian cancer [ 61 ], which may be an indicator of differential role of BRCA1 and BRCA2 in the pathogenesis of these diseases. Previous studies have already suggested mechanisms of how DNA damage may trigger immune response [ 72 , 73 ]; however, the question of why its intensity is higher in ovarian rather than in breast cancer remains open.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Arakelyan

Melkonyan

Hakobyan

et al. 2021

IJMS

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Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype “portrayal” with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Arakelyan

Melkonyan

Hakobyan

et al. 2021

IJMS

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“…Generally, the DDR pathway contains eight sub-pathways that can be divided into two main mechanisms. The pathways initiated in response to single-stranded DNA damage include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and single-stranded DNA binding (SSB), while the pathways activated during doublestranded DNA damage include nonhomologous end joining (NHEJ), homologous recombination (HR), the Fanconi anemia (FA) pathway and double-strand break repair (DSB) (13)(14)(15). All of the sub-pathways above are connected to each other to form a network that induces the DDR pathway in response to DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Activation of the DDR Pathway Leads to the Down-Regulation of the TGFβ Pathway and a Better Response to ICIs in Patients With Metastatic Urothelial Carcinoma

et al. 2021

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Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of metastatic urothelial carcinoma (mUC), a dominant type of bladder cancer (BC). Previous studies have shown an association between gene mutations in the DNA damage response (DDR) pathway and the immunotherapy response in mUC but have neglected the effect of the activation level of the DDR pathway on the ICI response in mUC. A published immunotherapy cohort with genome, transcriptome and survival data for 348 mUC patients was used. An external cohort (The Cancer Genome Atlas Bladder Cancer) and the GSE78220 cohort were used for validation. The activation level of the DDR pathway was quantified using single-sample gene set enrichment analysis (ssGSEA). Further analysis on the genome, immunogenicity, and the immune microenvironment was conducted using the DDR ssGSEA enrichment score-high (DSSH) group and the DDR ssGSEA enrichment score-low (DSSL) group. In the mUC cohorts, the DSSH group was associated with longer overall survival times (P=0.026; Hazard ratio=0.67; 95%CI: 0.46−0.95). The DSSH group was also associated with higher tumor mutation burden, neoantigen load, immune-activated cell patterns, and immune-related gene expression levels. The GSEA results indicated an immune activation state in DSSH group, which correlated with a down-regulation in the transforming growth factor β receptor signaling pathway. Our study suggests that the activation level of the DDR pathway may be a novel predictive marker for immunotherapy efficacy in patients with mUC.

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“…The prominent role of ATM is in DDR [54], especially in the DSBR mechanism and cell redox balance. In A-T, the activation of microglia and neurotoxic cytokine secretion are caused by the accumulation of cytoplasmic single stranded/double stranded self-DNA which is recognized by the innate immune system due to DNA repair defects [118,119]. Recent studies give insight into this issue.…”

Section: A-tmentioning

confidence: 99%

DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease

Wang

Lautrup

Caponio

et al. 2021

IJMS

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DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.

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DNA Damage Response and Immune Defense

Cited by 87 publications

References 199 publications

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

Activation of the DDR Pathway Leads to the Down-Regulation of the TGFβ Pathway and a Better Response to ICIs in Patients With Metastatic Urothelial Carcinoma

DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease

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