C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex.

MRE11 nuclease forms a trimeric complex (MRN) with RAD50 and NBS1 and plays a central role in preventing genomic instability. When DNA double-strand breaks (DSBs) occur, MRN is quickly recruited to the damage site and initiates DNA end resection; accordingly, MRE11 must be tightly regulated to avoid inefficient repair or nonspecific resection. Here, we show that MRE11 and RAD50 form a complex (MRC) with C1QBP, which stabilizes MRE11/RAD50, while inhibiting MRE11 nuclease activity by preventing its binding to DNA or chromatin. Upon DNA damage, ATM phosphorylates MRE11-S676/S678 to quickly dissociate the MRC complex. Either excess or insufficient C1QBP impedes the recruitment of MRE11 to DSBs and impairs the DNA damage response. C1QBP is highly expressed in breast cancer and positively correlates with MRE11 expression, and the inhibition of C1QBP enhances tumor regression with chemotherapy. By influencing MRE11 at multiple levels, C1QBP is, thus, an important player in the DNA damage response.

Tumor mutational burden adjusted by neutrophil-to-lymphocyte ratio serves as a potential biomarker for atezolizumab-treated patients with extensive stage small cell lung cancer.

BACKGROUND: There is a desperate for the identification of more accurate and efficient biomarkers for ICI responses in patients with SCLC. METHODS: The data of our study was obtained from IMpower133 study. A total of 202 patients with SCLC received the treatment of placebo plus carboplatin plus etoposide (EC) while a total of 201 patients with SCLC received the treatment of atezolizumab plus EC. Overall survival (OS) was compared using Kaplan Meier analyses. Univariate and multivariate Cox regression analysis were used to determine independent prognostic variables affecting OS in patients with SCLC. RESULTS: We have demonstrated that a higher TMB adjusted by a lower neutrophil-to-lymphocyte ratio (NLR) is significantly correlated with improved OS, in patients with SCLC subject to either atezolizumab or placebo (P = 0.001 for atezolizumab and P = 0.034 for placebo). Moreover, Cox model showed that TMB < 10 mut/Mb adjusted by NLR ≥ median was an independent factor of OS for atezolizumab-treated SCLC patients (hazard ratio [HR], 2.82; 95% confidence interval; 1.52-5.24; P = 0.001). Both univariate and multivariate cox regression analysis showed that for patients with SCLC harboring low NLR and high TMB, survival is significantly longer in those treated with atezolizumab than those treated with placebo. Survival benefit is significantly higher in atezolizumab-treated patients with SCLC than those treated with placebo (P = 0.018 for TMB cutoff = 10 mut/Mb, P = 0.034 for TMB cutoff = 16 mut/Mb). CONCLUSION: Our findings provide a promising insight into the utility of NLR-adjusted TMB in the prognosis and immune responses in patients with SCLC.

Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.

Parkinson's Disease Derived Exosomes Aggravate Neuropathology in SNCA*A53T Mice.

OBJECTIVE: Accumulation of α-synuclein (α-syn) in neurons is a prominent feature of Parkinson's disease (PD). Recently, researchers have considered that extracellular vesicles (EVs) may play an important role in protein exportation and propagation, and α-syn-containing EVs derived from the central nervous system (CNS) have been detected in peripheral blood. However, mechanistic insights into CNS-derived EVs have not been well-described. METHODS: Likely neurogenic EVs were purified from the plasma of PD patients and healthy controls using a well-established immunoprecipitation assay with anti-L1CAM-coated beads. A Prnp-SNCAA53T transgenic PD mouse model was used to evaluate the neuronal pathology induced by PD-derived L1CAM-purified EVs. EV-associated microRNA (miRNA) profiling was used to screen for altered miRNAs in PD-derived L1CAM-purified EVs. RESULTS: PD patient-derived L1CAM-purified (likely neurogenic) EVs facilitated α-syn pathology and neuron loss in Prnp-SNCAA53T transgenic PD mice. The miRNA, novel_miR_44438, was significantly increased in the PD group, which promoted α-syn accumulation and neuronal degeneration in a dose-dependent manner. Novel _miR_44438 directly targets NDST1 mRNA and inhibits the function of heparan sulfate, thus preventing exosome biogenesis and α-syn release from exosomes. INTERPRETATION: Novel_miR_44438 in PD-derived L1CAM-purified EVs inhibits the α-syn efflux from neurons thereby promoting the pathological accumulation and aggregation of α-syn. ANN NEUROL 2022;92:230-245.

Serum brain-derived neurotrophic factor in coronary heart disease: Correlation with the T helper (Th)1/Th2 ratio, Th17/regulatory T (Treg) ratio, and major adverse cardiovascular events.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) exerts protective roles against dyslipidemia, atherosclerosis, and inflammation in cardiovascular diseases; meanwhile, it retards CD4+ T cell differentiation into T helper (Th)1 and Th17 cells. Hence, this study aimed to investigate the linkage of serum BDNF with Th1/Th2 ratio, Th17/regulatory T (Treg) ratio, and major adverse cardiovascular events (MACE) risk in the coronary heart disease (CHD) patients. METHODS: This prospective study detected serum BDNF in 210 CHD patients, 50 disease controls (DCs), and 50 healthy controls (HCs) using an enzyme-linked immunosorbent assay. For CHD patients only, the proportion of Th1, Th2, Th17, and Treg cells in blood CD4+ T cells was calculated by flow cytometry. RESULTS: The BDNF varied among CHD patients, DC, and HC (p < 0.001). Specifically, BDNF was declined in CHD patients compared with DCs (p < 0.001) and HCs (p < 0.001). In CHD patients, BDNF was negatively related to Th1 cells (p = 0.031), Th1/Th2 ratio (p = 0.026), Th17 cells (p = 0.001), and Th17/Treg ratio (p = 0.002). Concerning the prognosis, BDNF was reduced in patients with MACE occurrence compared to patients without MACE occurrence (p = 0.006). Furthermore, BDNF showed a trend (lacked statistical significance) to relate to longer MACE-free survival (p = 0.059). Besides, BDNF was related to the absence of obesity (p = 0.019), decreased total cholesterol (p = 0.043), low-density lipoprotein cholesterol (p = 0.019), C-reactive protein (p = 0.012), and Gensini score (p = 0.005). CONCLUSION: Serum BDNF negatively correlates with Th1/Th2 ratio, Th17/Treg ratio, and estimates lower MACE risk in CHD patients.

Clinical value of long non-coding RNA KCNQ1OT1 in estimating the stenosis, lipid level, inflammation status, and prognostication in coronary heart disease patients.

OBJECTIVE: Long non-coding RNA KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) could regulate lipid metabolism, vascular smooth muscle cell function, inflammation, and atherosclerosis. This study aimed to evaluate whether lncRNA KCNQ1OT1 could serve as a biomarker for reflecting coronary heart disease (CHD) patients' disease situation and prognosis. METHODS: LncRNA KCNQ1OT1 expression was determined in peripheral blood mononuclear cells from 267 CHD patients, 50 disease controls (DCs) (unexplained chest pain), and 50 healthy controls (HCs) by the RT-qPCR method. TNF-α, IL-17A, VCAM-1, and ICAM-1 were determined by the ELISA procedure in serum from CHD patients only. The mean (95% confidential interval) follow-up duration was 16.0 (15.3-16.8) months. RESULTS: LncRNA KCNQ1OT1 was highest in CHD patients, followed by DCs, and lowest in HCs (p < 0.001). LncRNA KCNQ1OT1 could distinguish the CHD patients from DCs (area under the curve [AUC]: 0.757) and from the HCs (AUC: 0.880). LncRNA KCNQ1OT1 was positively associated with triglyceride (p = 0.026), low-density lipoprotein cholesterol (p = 0.023), cardiac troponin I (p = 0.023), and C-reactive protein (p = 0.001). Besides, lncRNA KCNQ1OT1 was also positively linked with the Gensini score (p = 0.008). Furthermore, lncRNA KCNQ1OT1 was positively related to the TNF-α (p < 0.001), IL-17A (p = 0.008), and VCAM-1 (p = 0.003). LncRNA KCNQ1OT1 was elevated in CHD patients with MACE compared to those without MACE (p = 0.006); moreover, lncRNA KCNQ1OT1 high was associated with shorter MACE-free survival (p = 0.018). CONCLUSION: Circulating lncRNA KCNQ1OT1 expression not only reflects the stenosis degree, blood lipid level, and inflammation status but also predicts the MACE risk, while a large-scale study is needed for verification.

Extracellular ATP promotes angiogenesis and adhesion of TNBC cells to endothelial cells via upregulation of CTGF.

Our previous works have indicated that extracellular ATP is an important prometastasis factor. However, the molecular mechanism involved needs to be further studied. We demonstrated that extracellular ATP treatment could upregulate the expression of connective tissue growth factor (CTGF) in both triple-negative breast cancer (TNBC) cells and endothelial cells (ECs). Extracellular ATP stimulated the migration of TNBC cells and ECs, and angiogenesis of ECs via the P2Y2--YAP-CTGF axis. Furthermore, we demonstrated that adenosine triphosphate (ATP) stimulated TNBC cell adhesion to ECs and transmigration through the EC layer via CTGF by upregulation of integrin ß1 on TNBC cells and VCAM-1 on ECs. Both apyrase (ATP-diphosphohydrolase) and CTGF shRNA treatments could inhibit the metastasis of inoculated tumors to lung and liver in a mouse model, and these treated tumors had fewer blood vessels. Collectively, our data indicated that extracellular ATP promotes tumor angiogenesis and the interactions between TNBC cells and ECs through upregulation of CTGF, thereby stimulating TNBC metastasis. The pleiotropic effects of ATP in angiogenesis and cell adhesion suggest that extracellular ATP or CTGF could be an effective target for TNBC therapy.

Extracellular ATP promotes breast cancer invasion and epithelial-mesenchymal transition via hypoxia-inducible factor 2α signaling.

Extracellular ATP has been shown to play an important role in invasion and the epithelial-mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia-inducible factor (HIF) signaling and upregulate hypoxia-inducible factor 1/2α (HIF-1/2α) expression. After knocking down HIF-1/2α using siRNA, we found that ATP-driven invasion and EMT were significantly attenuated via HIF2A-siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF-2α direct targets, among which lysyl oxidase-like 2 (LOXL2) and matrix metalloproteinase-9 (MMP-9) mediated ATP-driven invasion, and E-cadherin and Snail mediated ATP-driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF-2α and mediate ATP-driven HIF-2α upregulation. Furthermore, we demonstrated that expressions of HIF-2α and its target proteins could be regulated via ATP by AKT-PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF-2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP-HIF-2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF-2α signaling, which may be a potential target for future anti-metastasis therapy.

Super-enhancers: Implications in gastric cancer.

Gastric cancer (GC) is the fifth most prevalent malignancy and the third leading cause of cancer-related mortality globally. Despite intensive efforts to enhance the efficiencies of various therapeutics (chemotherapy, surgical interventions, molecular-targeted therapies, immunotherapies), the prognosis for patients with GC remains poor. This might be predominantly due to the limited understanding of the complicated etiology of GC. Importantly, epigenetic modifications and alterations are crucial during GC development. Super-enhancers (SEs) are a large cluster of adjacent enhancers that greatly activate transcription. SEs sustain cell-specific identity by enhancing the transcription of specific oncogenes. In this review, we systematically summarize how SEs are involved in GC development, including the SE landscape in GC, the SE target genes in GC, and the interventions related to SE functions for treating GC.

Long non-coding RNAs in non-small cell lung cancer: implications for preventing therapeutic resistance.

Lung cancer has the highest mortality and morbidity rates among all cancers worldwide. Despite many complex treatment options, including radiotherapy, chemotherapy, targeted drugs, immunotherapy, and combinations of these treatments, efficacy is low in cases of resistance to therapy, metastasis, and advanced disease, contributing to low overall survival. There is a pressing need for the discovery of novel biomarkers and therapeutic targets for the early diagnosis of lung cancer and to determine the efficacy and outcomes of drug treatments. There is now substantial evidence for the diagnostic and prognostic value of long noncoding RNAs (lncRNAs). This review briefly discusses recent findings on the roles and mechanisms of action of lncRNAs in the responses to therapy in non-small cell lung cancer.

Circulating HDAC4 reflects lipid profile, coronary stenosis and inflammation in coronary heart disease patients.

Aim: To investigate the clinical value of HDAC4 in coronary heart disease (CHD) patients. Methods: The serum HDAC4 levels were determined by ELISA in 180 CHD patients and 50 healthy controls. Results: HDAC4 was decreased in CHD patients compared with healthy controls (p < 0.001). HDAC4 was negatively linked with serum creatinine (p = 0.014), low-density lipoprotein cholesterol (p = 0.027) and C-reactive protein (p = 0.006) in CHD patients. Moreover, HDAC4 was inversely related to TNF-α (p = 0.012), IL-1ß (p = 0.002), IL-6 (p = 0.034), IL-17A (p = 0.023), VCAM1 (p = 0.014) and Gensini score (p = 0.001). Unfortunately, neither HDAC4 high (vs low) (p = 0.080) nor HDAC4 quartile (p = 0.268) estimated major adverse cardiovascular event risk. Conclusion: Circulating HDAC4 levels have disease monitoring value but are less valuable in estimating prognosis in CHD patients.

What was this article about? This study aimed to assess the clinical significance of identifying a marker named histone deacetylase 4 (HDAC4) in coronary heart disease (CHD) patients. What was done? Blood was taken from 180 CHD patients and 50 healthy controls, and their blood HDAC4 levels were evaluated. What were the results? HDAC4 levels were higher in CHD patients than in the controls. The CHD patients with a higher HDAC4 level had good kidney health and lower lipid profile, milder inflammation, good vascular status and less narrowing in their blood vessels. However, the HDAC4 level was not found to predict the risk of future cardiovascular disease. What do the results mean? A higher HDAC4 level in the blood of CHD patients suggests a better symptomatic disease status.

Increased SEMA6B expression as a potential prognostic and immune cell infiltration biomarker in thyroid cancer patients.

BACKGROUND: Even today, thyroid cancer (THCA) remains an important threat to global health. For THCA patients, differentiated thyroid cancer is the most commonly identified pathological subtype, and those diagnosed with papillary thyroid cancer generally have good overall prognosis. For poorly differentiated subtype THCA, patients have aggressive disease course, higher risk of distant organ metastasis and inferior overall prognosis. METHODS: RNA-seq data from TCGA and GTEx databases are collected and analyzed via R. The correlation between SEMA6B expression level and pathological as well as clinical parameters of THCA patients was respectively investigated. Gene expression profiling and subsequent functional clustering analysis was the performed utilizing GSEA. The receiver operating characteristic (ROC) curve was utilized to evaluate the diagnostic value of SEMA6B expression. RESULTS: Increased SEMA6B expression was characteristic in THCA tumor samples and was associated with specific pathologic and clinical features for TCHA patients. Univariate and multivariate analysis indicated that SEMA6B was independent predictive marker for THCA patients' prognosis. Gene expression profiling and functional clustering analysis suggested that SEMA6B high-expression was related with increased expression of multiple signal pathways and signatures of multiple immune cell infiltration. CONCLUSIONS: In this study, through bioinformatic analysis and clinical data investigation, we demonstrated the potential value of SEMA6B as diagnostic and prognostic marker in THCA patient treatment.

Inflammatory cytokine-regulated LNCPTCTS suppresses thyroid cancer progression via enhancing Snail nuclear export.

Lymph node metastases are commonly observed in diverse malignancies where they promote cancer progression and poor outcomes, although the molecular basis is incompletely understood. Thyroid cancer is the most prevalent endocrine neoplasm characterized by high frequency of lymph node metastases. Here, we uncover an inflammatory cytokines-controlled epigenetic program during thyroid cancer progression. LNCPTCTS acts as a novel tumor suppressive lncRNA with remarkably decreased expression in thyroid cancer specimens, especially in metastatic lymph nodes. Inflammatory cytokines TNFα or CXCL10, which are released from tumor microenvironment (TME), impair binding capabilities of the transcription factor (TF) EGR1 to the LNCPTCTS promoter and reduce the lncRNA expression in cells. Notably, LNCPTCTS binds to eEF1A2 protein and facilitates the interaction between eEF1A2 and Snail, which promotes Snail nucleus export via the RanGTP-Exp5-aa-tRNA-eEF1A2 complex. Loss of LNCPTCTS in tumors leads to accumulation of Snail in the nucleus, suppressed transcription of E-cadherin and PEBP1, reduced E-cadherin and PEBP1 protein levels, and activated epithelial-mesenchymal transition and MAPK signaling. Our results reveal what we believe to be a novel paradigm between TME and epigenetic reprogram in cancer cells which drives lymph node metastases, therefore illuminating the suitability of LNCPTCTS as a targetable vulnerability in thyroid cancer.

Serum ITIH4 in coronary heart disease: a potential anti-inflammatory biomarker related to stenosis degree and risk of major adverse cardiovascular events.

Aim: This study aimed to investigate the correlation of ITIH4 with inflammatory cytokines, stenosis degrees and prognosis in coronary heart disease (CHD) patients. Methods: Serum ITIH4 levels of 300 CHD patients and 30 controls, together with levels of TNF-α, IL-6, IL-8 and IL-17A of CHD patients, were determined using ELISA. Results: Serum ITIH4 was reduced in CHD patients versus controls (p < 0.001). ITIH4 was negatively linked with TNF-α, IL-6, IL-8, IL-17A, C-reactive protein, serum creatinine and Gensini score in CHD patients (all p < 0.050). ITIH4 quartile level negatively correlated with the cumulative major adverse cardiovascular event rate (p = 0.041). Conclusion: Serum ITIH4 may serve as an anti-inflammatory biomarker that negatively associates with stenosis degree and major adverse cardiovascular event risk in CHD patients.

What is this article about? This study aimed to find the clinical value of measuring the protein ITIH4 in patients with coronary heart disease (CHD). What was done? A total of 300 CHD patients and 30 non-CHD people (with chest pain or suspected CHD symptoms) were enrolled in this study. Blood ITIH4 levels of all people were detected. What were the results? Blood ITIH4 levels were lower in CHD patients compared with non-CHD people. In CHD patients, a high level of ITIH4 was associated with low inflammation, reduced vessel narrowness and a good prognosis. What do the results mean? Blood ITIH4 serves as an anti-inflammatory biomarker, whose high level represents better conditions in CHD patients.

The risk variant rs11836367 contributes to breast cancer onset and metastasis by attenuating Wnt signaling via regulating NTN4 expression.

Most genome-wide association study (GWAS)-identified breast cancer-associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at the NTN4 locus (12q22) and NTN4 gene in breast cancer etiology. We find that rs11836367 is the more likely causal variant, disrupting enhancer activity in both enhancer reporter assays and endogenous genome editing experiments. The protective T allele of rs11837367 increases the binding of GATA3 to the distal enhancer and up-regulates NTN4 expression. In addition, we demonstrate that loss of NTN4 gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that NTN4, as a tumor suppressor, can attenuate the Wnt signaling pathway by directly binding to Wnt ligands. Our findings bridge the gaps among breast cancer-associated single-nucleotide polymorphisms, transcriptional regulation of NTN4, and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.

Association Between Triglyceride-Glucose Index and the Risk of Type 2 Diabetes Mellitus in an Older Chinese Population Aged Over 75 Years.

Background: The association between the triglyceride-glucose (TyG) index and type 2 diabetes mellitus (T2DM) in older adults has not been fully understood. This research aims to explore the association between the TyG index and the incidence of T2DM in an older Chinese population aged over 75 years. Methods: This longitudinal analysis study was performed based on a database from a health check screening program in China. The participants were stratified based on the quintile ranges of the TyG index (Q1 to Q5 groups). T2DM was defined as fasting plasma glucose (FPG) ≥ 7.00 mmol/L and/or self-reported T2DM. The cumulative incidences of T2DM in various quintile groups were estimated by the Kaplan-Meier method. The Cox proportional hazard model was used to examine the independent impact of the TyG index on the risk of T2DM during the follow-up period. Subgroup analysis was performed by gender and BMI to further validate the credibility of the results. Results: During the follow-up period, a total of 231 new-onset T2DM cases were recorded among the 2,571 individuals aged over 75 years. After adjusting confounding factors, elevated TyG index independently indicated a higher risk of T2DM (HR = 1.89; 95% CI, 1.47-2.44; p < 0.01). Higher TyG index quintile groups (Q3 to Q5) also presented with a higher risk of T2DM (hazard ratio (HR) = 1.36, 1.44, and 2.12, respectively) as compared with the lowest quintile group (Q1). Subgroup analysis showed that increased TyG index led to a higher risk of T2DM with HR = 2.35 (95% CI, 1.73-3.19), 1.90 (95% CI, 1.27-2.83), 2.95 (95% CI, 1.94-4.50), and 1.72 (95% CI, 1.25-2.35) in male subgroup, female subgroup, BMI < 24 kg/m2 subgroup, and BMI ≥ 24 kg/m2 subgroup, respectively. Conclusions: Triglyceride-glucose index independently correlated with the risk of incident T2DM in Chinese adults aged over 75 years. The TyG index might be useful in monitoring T2DM in the older populations.

PCAF/GCN5-Mediated Acetylation of RPA1 Promotes Nucleotide Excision Repair.

The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway. DNA-PK phosphorylates and activates PCAF upon UV damage and consequently promotes the acetylation of RPA1. Moreover, the acetylation of RPA1 is tightly regulated by HDAC6 and SIRT1. Together, our results demonstrate that the K163 acetylation of RPA1 plays a key role in the repair of UV-induced DNA damage and reveal how the specific RPA1 modification modulates the choice of distinct DNA repair pathways.