scholarly journals Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

2010 ◽  
Vol 107 (5) ◽  
pp. 2207-2212 ◽  
Author(s):  
Hila Barash ◽  
Eitan R. Gross ◽  
Yifat Edrei ◽  
Ezra Ella ◽  
Ariel Israel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Liver Regeneration ◽  
Chronic Inflammation ◽  
Dna Damage Response ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Dna Breaks ◽  
Double Strand Dna Breaks ◽  
Damage Response

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence.

scholarly journals Dissecting the Molecular Mechanisms of Aneuploidy in Acute Myeloid Leukemia By Next Generation Sequencing

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1028-1028
Author(s):  
Giorgia Simonetti ◽  
Antonella Padella ◽  
Anna Ferrari ◽  
Viviana Guadagnuolo ◽  
Elisa Zago ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Chromosome Organization ◽  
Single Nucleotide ◽  
Damage Response ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia (AML) is a heterogeneous malignancy characterized by the expansion of myeloid precursor cells with limited or abnormal differentiation capacity. A relatively common event in AML is represented by chromosome gain or loss. Numerical chromosome abnormalities, which define aneuploidy, have a detrimental effect in primary non-malignant cells, since they dramatically reduce cellular fitness. However, evidence suggests that they have a causative role in tumorigenesis and are well tolerated in transformed cells belonging to the myeloid lineage. Aim of the study is to elucidate the pathogenic mechanisms causing and sustaining aneuploidy in AML in order to find novel potential therapeutic targets. A panel of genetic alterations was analyzed on 886 AML cases at Seràgnoli Institute in Bologna between 2002 and 2013. Among them, 31 samples were subjected to whole exome sequencing (WES, Illumina Hiseq2000). Raw data were processed with WES Pipeline web tool for variants detection. Gene expression profiling (GEP, Affymetrix) was performed on bone marrow cells from 49 AML patients at diagnosis with more than 80% blast cells, including 22 aneuploid cases (carrying monosomy, trisomy or a monosomal karyotype) and 27 cases with normal karyotype. The aneuploid status was confirmed by single nucleotide polymorphism (SNP) array. WES analysis of 13 aneuploid and 12 euploid AML cases revealed a significantly higher median value of genetic variants and mutated genes in aneuploid compared with euploid samples (aneuploid vs. euploid: median of variants, 30 vs. 20 (p=0.02) including nonsynonimous single nucleotide variants, frameshift insertions and deletions, stopgains; median of mutated genes, 25 vs. 17 (p=0.05); details will be presented at the meeting). Noticeably, by gene ontology analysis of mutated genes in the aneuploid cohort we observed a strong enrichment in genes regulating cell cycle, including chromosome organization (p=5.4x10-4) and mitotic sister chromatid cohesion (p=6.98x10-4), and chromatin modification (p=1.3x10-4), with most of the variants being not annotated in the COSMIC database. Euploid samples were enriched for mutations affecting genes involved in cytoskeleton (p=1.6x10-3) and metabolic activities (p=1.9x10-3). A number of genes mutated in the aneuploid cases belong to the APCCdc20 complex and localize on chromosomes generally spared by aneuploidy, supporting the key role of the identified aberrations in the molecular mechanisms leading to numerical chromosome abnormalities. Among several mutations predicted as “drivers” by DOTS-Finder tool (CCDC144NL, DNMT3A, GXYLT1, MESP1, TPRX1,TPTE, ZNF717), we defined some candidates involved in cell cycle regulation and DNA replication. Functional analysis are ongoing. Furthermore, a tumor suppressor function was associated with mutated genes involved in the DNA repair process. In our WES analysis, we identified a subgroup of genes linked to DNA damage response, including TP53, which are preferentially mutated in the aneuploid cohort. Since P53 is a limiting-factor in aneuploidy-induced tumorigenesis, we analyzed the mutational status in a larger cohort of AML patients by Next Generation sequencing (NGS) and Sanger sequencing. Interestingly, we identified TP53 mutations in 15/58 aneuploid vs. 1/36 euploid cases (p=3.8x10-3). Finally, differential expression of genes involved in DNA damage and integrity checkpoints was identified by GEP of aneuploid and euploid AML samples. Previous evidence showed that loss of the spindle checkpoint gene BUB1B induces aneuploidy and predisposes to tumorigenesis. Our data, obtained by integrated NGS and GEP approaches, support a causal link between mutations in a panel of genes involved in cell cycle control/chromosome organization and aneuploidy in AML. Genetic and transcriptional alterations of genes regulating DNA damage response were detected in our AML cohort, suggesting novel molecular mechanisms for the acquisition and/or maintenance of the aneuploid condition and consequently, of leukemogenesis. The results indicate that the identified genomic aberrations likely drive chromosome gain and/or loss in AML by cooperating with alterations affecting different pathways, in order to overcome the unfitness barrier induced by aneuploidy. Supported by: FP7 NGS-PTL project, ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi). Disclosures Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

scholarly journals Home and Away: The Role of Non-Coding RNA in Intracellular and Intercellular DNA Damage Response

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1475
Author(s):  
Annabelle Shaw ◽  
Monika Gullerova
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Therapeutic Potential ◽  
Dna Breaks ◽  
Double Strand Dna Breaks ◽  
Non Coding Rna ◽  
Damage Response ◽  
Recent Developments ◽  
Vital Component ◽  
Long Non Coding Rna

Non-coding RNA (ncRNA) has recently emerged as a vital component of the DNA damage response (DDR), which was previously believed to be solely regulated by proteins. Many species of ncRNA can directly or indirectly influence DDR and enhance DNA repair, particularly in response to double-strand DNA breaks, which may hold therapeutic potential in the context of cancer. These include long non-coding RNA (lncRNA), microRNA, damage-induced lncRNA, DNA damage response small RNA, and DNA:RNA hybrid structures, which can be categorised as cis or trans based on the location of their synthesis relative to DNA damage sites. Mechanisms of RNA-dependent DDR include the recruitment or scaffolding of repair factors at DNA break sites, the regulation of repair factor expression, and the stabilisation of repair intermediates. DDR can also be communicated intercellularly via exosomes, leading to bystander responses in healthy neighbour cells to generate a population-wide response to damage. Many microRNA species have been directly implicated in the propagation of bystander DNA damage, autophagy, and radioresistance, which may prove significant for enhancing cancer treatment via radiotherapy. Here, we review recent developments centred around ncRNA and their contributions to intracellular and intercellular DDR mechanisms.

scholarly journals Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiate the DNA damage response and repair

2020 ◽  
Author(s):  
Fanbiao Meng ◽  
Minxian Qian ◽  
Bin Peng ◽  
Xiaohui Wang ◽  
Linyuan Peng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Cultured Cells ◽  
Synergistic Action ◽  
Dna Breaks ◽  
Spatiotemporal Regulation ◽  
Double Strand Dna Breaks ◽  
Damage Response ◽  
Defective Dna Repair

SummaryThe DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair.

scholarly journals GC-Rich Extracellular DNA Induces Oxidative Stress, Double-Strand DNA Breaks, and DNA Damage Response in Human Adipose-Derived Mesenchymal Stem Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Svetlana Kostyuk ◽  
Tatiana Smirnova ◽  
Larisa Kameneva ◽  
Lev Porokhovnik ◽  
Anatolij Speranskij ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Dna Damage ◽  
Mesenchymal Stem Cells ◽  
Dna Damage Response ◽  
Extracellular Dna ◽  
Dna Breaks ◽  
Rt Pcr ◽  
Double Strand Dna Breaks ◽  
Damage Response

Background. Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases. CfDNA is substantially enriched in its GC-content as compared with human genomic DNA.Principal Findings. Exposure of haMSCs to GC-DNA induces short-term oxidative stress (determined with H2DCFH-DA) and results in both single- and double-strand DNA breaks (comet assay andγH2AX, foci). As a result in the cells significantly increases the expression of repair genes (BRCA1(RT-PCR), PCNA (FACS)) and antiapoptotic genes (BCL2(RT-PCR and FACS),BCL2A1,BCL2L1, BIRC3, andBIRC2(RT-PCR)). Under the action of GC-DNA the potential of mitochondria was increased. Here we show that GC-rich extracellular DNA stimulates adipocyte differentiation of human adipose-derived mesenchymal stem cells (haMSCs). Exposure to GC-DNA leads to an increase in the level of RNAPPARG2andLPL(RT-PCR), in the level of fatty acid binding protein FABP4 (FACS analysis) and in the level of fat (Oil Red O).Conclusions. GC-rich fragments in the pool of cfDNA can potentially induce oxidative stress and DNA damage response and affect the direction of mesenchymal stem cells differentiation in human adipose—derived mesenchymal stem cells. Such a response may be one of the causes of obesity or osteoporosis.

ILF2-YB1 Protein Interaction Modulates RNA Splicing to Induce Resistance to Chemotherapy in High Risk Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 359-359
Author(s):  
Matteo Marchesini ◽  
Yamini Ogoti ◽  
Elena Fiorini ◽  
Marianna D'anca ◽  
Paola Storti ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Copy Number ◽  
Research Funding ◽  
Repair Pathway ◽  
Dna Breaks ◽  
Double Strand Dna Breaks ◽  
Damage Response ◽  
Cellular Replication

Abstract The 1q21 amplification, which occurs in approximately 40% of de novo and 70% of relapsed MM, is among the most frequent chromosomal aberrations in multiple myeloma (MM) patients and is considered a very high-risk genetic feature that is especially correlated with disease progression and drug resistance. To uncover novel 1q21 MM-critical genes, we first identified a list of 78 potential 1q21 drivers, which were located in the minimal common region of amplification of 254 MM samples and showed copy number-driven expression. These 78 candidates were then subjected to an shRNA screen to identify those genes involved in selective death and/or growth inhibition of MM cells carrying the 1q21 amplification. Using this approach, we identified and functionally validated the Interleukin-2 enhancer binding factor 2 (ILF2) as one of key 1q21 amplification-specific genes. ILF2 downregulation in 1q21-amplified MM cells resulted in multinucleated phenotypes and abnormal nuclear morphologies, findings that are consistent with the DNA damage-induced genomic instability that is associated with DNA repair defects that occur during cellular replication. Correspondingly, ILF2 downregulation was associated with a significant increase in the activation of the ATM (but not ATR or DNA-PK) pathway and accumulation of gH2AX foci, which are indicative of double-strand DNA breaks, and resulted in caspase 3-mediated apoptosis. Therefore, we sought to determine whether ILF2 is involved in the genome damage repair that occurs during cellular replication. To this end, we evaluated whether ILF2 depletion could affect the efficiency of non-homologous end joining (NHEJ) or homologous recombination (HR), the two major repair pathways in mammalian cells. We observed a profound impairment of HR in ILF2-depleted cells (p=0.038), whereas NHEJ was unaltered after ILF2 downregulation. Conversely, enforced ILF2 expression significantly enhanced HR efficiency in MM cells (p=0.008). To further support the role of ILF2 in the regulation of the DNA repair pathway in MM cells, we evaluated whether ILF2 downregulation increased MM sensitivity to DNA-damaging agents routinely used in the treatment of MM. Employing the interstrand crosslinker melphalan as an instigator of double-strand DNA breaks, we found that ILF2-depleted MM cells subjected to continuous melphalan treatment showed increased accumulation of γH2AX and apoptosis. Consistent with these findings, elevated ILF2 expression significantly correlated with poor survival in MM patients treated with high-dose melphalan followed by tandem autologous transplantation (n=256, p=0.01). Mechanistically, mass spectrometry analysis showed that ILF2 interacted with numerous RNA binding proteins directly involved in the regulation of DNA damage response by modulating alternative splicing of specific pre-mRNAs. RNA-sequencing experiments confirmed that ILF2 depletion resulted in aberrant splicing of genes involved in the DNA repair pathway, including ERCC1, FANCD2, and EXO1. RNA immunoprecipitation sequencing experiments showed that ILF2 directly bound to transcripts involved in the regulation of the HR pathway, including components of BRCA1 protein complex. Furthermore, in an attempt to dissect the ILF2 protein interacting network involved in the DNA repair regulation in response to DNA damage activation, we found that ILF2 mediated drug resistance in a dose-dependent manner by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65 to promote mRNA processing and stabilization of DNA repair genes, including FANCD2 and EXO1, in response to DNA damage. In conclusion, our study reveals an intimate relationship among 1q21 amplification, mRNA splicing, and DNA repair in the control of DNA damage response in MM. Given that 1q21 amplification is one of the most frequent copy number alterations in cancer, synthetic lethality approaches based on targeting gain-of-functions associated with ILF2 may have a broad spectrum of applications to potentiate the sensitivity of cancer cells to chemotherapeutic agents. Disclosures Giuliani: Janssen: Research Funding; Celgene: Research Funding.

scholarly journals HIV Vpr Modulates the Host DNA Damage Response at Two Independent Steps to Damage DNA and Repress Double-Strand DNA Break Repair

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Donna Li ◽  
Andrew Lopez ◽  
Carina Sandoval ◽  
Randilea Nichols Doyle ◽  
Oliver I. Fregoso
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Signaling Cascade ◽  
Human Pathogens ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
Damage Response ◽  
Hiv 1

ABSTRACT The DNA damage response (DDR) is a signaling cascade that is vital to ensuring the fidelity of the host genome in the presence of genotoxic stress. Growing evidence has emphasized the importance of both activation and repression of the host DDR by diverse DNA and RNA viruses. Previous work has shown that HIV-1 is also capable of engaging the host DDR, primarily through the conserved accessory protein Vpr. However, the extent of this engagement has remained unclear. Here, we show that HIV-1 and HIV-2 Vpr directly induce DNA damage and stall DNA replication, leading to the activation of several markers of double- and single-strand DNA breaks. Despite causing damage and activating the DDR, we found that Vpr represses the repair of double-strand breaks (DSB) by inhibiting homologous recombination (HR) and nonhomologous end joining (NHEJ). Mutational analyses of Vpr revealed that DNA damage and DDR activation are independent from repression of HR and Vpr-mediated cell cycle arrest. Moreover, we show that repression of HR does not require cell cycle arrest but instead may precede this long-standing enigmatic Vpr phenotype. Together, our data uncover that Vpr globally modulates the host DDR at at least two independent steps, offering novel insight into the primary functions of lentiviral Vpr and the roles of the DNA damage response in lentiviral replication. IMPORTANCE The DNA damage response (DDR) is a signaling cascade that safeguards the genome from genotoxic agents, including human pathogens. However, the DDR has also been utilized by many pathogens, such as human immunodeficiency virus (HIV), to enhance infection. To properly treat HIV-positive individuals, we must understand how the virus usurps our own cellular processes. Here, we have found that an important yet poorly understood gene in HIV, Vpr, targets the DDR at two unique steps: it causes damage and activates DDR signaling, and it represses the ability of cells to repair this damage, which we hypothesize is central to the primary function of Vpr. In clarifying these important functions of Vpr, our work highlights the multiple ways human pathogens engage the DDR and further suggests that modulation of the DDR is a novel way to help in the fight against HIV.

scholarly journals HIV Vpr modulates the host DNA damage response at two independent steps to damage DNA and repress double-strand DNA break repair

2020 ◽  
Author(s):  
Donna Li ◽  
Andrew Lopez ◽  
Carina Sandoval ◽  
Randilea Nichols Doyle ◽  
Oliver I Fregoso
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Signaling Cascade ◽  
Human Pathogens ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
Damage Response ◽  
Hiv 1

ABSTRACTThe DNA damage response (DDR) is a signaling cascade that is vital to ensuring the fidelity of the host genome in the presence of genotoxic stress. Growing evidence has emphasized the importance of both activation and repression of the host DDR by diverse DNA and RNA viruses. Previous work has shown that HIV-1 is also capable of engaging the host DDR, primarily through the conserved accessory protein Vpr. However, the extent of this engagement has remained unclear. Here we show that HIV-1 and HIV-2 Vpr directly induce DNA damage and stall DNA replication, leading to the activation of several markers of double- and single-strand DNA breaks. Despite causing damage and activating the DDR, we found that Vpr repress the repair of double-strand breaks (DSB) by inhibiting homologous recombination (HR) and non-homologous end joining (NHEJ). Mutational analyses of Vpr revealed that DNA damage and DDR activation are independent from repression of HR and Vpr-mediated cell-cycle arrest. Moreover, we show that repression of HR does not require cell-cycle arrest but instead may precede this long-standing enigmatic Vpr phenotype. Together, our data uncover that Vpr globally modulates the host DDR at at least two independent steps; offering novel insight into the primary functions of lentiviral Vpr and the roles of the DNA damage response in lentiviral replication.IMPORTANCEThe DNA damage response (DDR) is a signaling cascade that safeguards the genome from genotoxic agents, including human pathogens. However, the DDR has also been utilized by many pathogens, such as Human Immunodeficiency Virus (HIV), to enhance infection. To properly treat HIV positive individuals, we must understand how the virus usurps our own cellular processes. Here, we have found that an important yet poorly-understood gene in HIV, Vpr, targets the DDR at two unique steps: it causes damage and activates DDR signaling, and it represses the ability of cells to repair this damage, which we hypothesize is central to the primary function of Vpr. In clarifying these important functions of Vpr, our work highlights the multiple ways human pathogens engage the DDR, and further suggests that modulation of the DDR may be a novel way to help in the fight against HIV.

MYC Inactivation Induces Tumor Regression through the Recovery of a Functional DNA Damage Response.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1534-1534
Author(s):  
Karen Rabin ◽  
Sylvie Giuriato ◽  
Suma Ray ◽  
Dean W. Felsher
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Tumor Cells ◽  
Dna Damage Response ◽  
Tumor Regression ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
Damage Response ◽  
Functional Dna

Abstract Cancer is caused by genetic events that result in the activation of oncogenes or the inactivation of tumor suppressor genes. Using the Tetracycline system, our laboratory has generated a transgenic mouse model in which MYC is conditionally overexpressed in hematopoietic cells, allowing us to turn MYC expression on and off at will. We have previously demonstrated that the inactivation of this single oncogene in an established and even highly invasive and metastatic lymphoma is sufficient to reverse cancer, suggesting that MYC may be an effective therapeutic target. In a variety of conditional oncogene models, we and others have found that tumor regression following oncogene inactivation involves similar phenomena, including cell cycle arrest, apoptosis, and differentiation of the tumor cells. The similarity in the regression process across a variety of different oncogenes and types of cancer strongly suggests the existence of a common signaling pathway following oncogene inactivation, which culminates in the cessation of cell proliferation and the induction of apoptosis and differentiation. Recently, we have demonstrated that MYC activation disrupts the repair of DNA breaks and results in genomic instability. We speculated that MYC inactivation may cause tumor regression by restoring the ability of tumor cells to recognize that they are genomically damaged, which could subsequently lead to the cell cycle arrest, differentiation and apoptosis that is generally observed. Indeed, we now report that upon MYC inactivation, tumor cells activate DNA damage signaling pathways and begin to repair their DNA breaks. We have found evidence for activation of a functional DNA damage response both by immunofluorescent staining for phosphorylated ATM and Mre11, which demonstrates foci formation following MYC inactivation; and by the Comet assay, which shows a quantitative decrease in severity of DNA breaks following MYC inactivation. Our results suggest that MYC inactivation may induce tumor regression at least in part through the restoration of a DNA damage checkpoint response.

scholarly journals Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Fanbiao Meng ◽  
Minxian Qian ◽  
Bin Peng ◽  
Linyuan Peng ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Cultured Cells ◽  
Dna Breaks ◽  
Spatiotemporal Regulation ◽  
Double Strand Dna Breaks ◽  
Damage Response ◽  
Mouse Cells ◽  
Defective Dna Repair

The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR in human and mouse cells. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair in humans and mice.

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