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1.
EMBO Rep ; 25(8): 3263-3275, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38866979

RESUMEN

As a hallmark of senescent cells, the derepression of Long Interspersed Elements 1 (LINE1) transcription results in accumulated LINE1 cDNA, which triggers the secretion of the senescence-associated secretory phenotype (SASP) and paracrine senescence in a cGAS-STING pathway-dependent manner. However, transcription factors that govern senescence-associated LINE1 reactivation remain ill-defined. Here, we predict several transcription factors that bind to human LINE1 elements to regulate their transcription by analyzing the conserved binding motifs in the 5'-untranslated regions (UTR) of the commonly upregulated LINE1 elements in different types of senescent cells. Further analysis reveals that PAX5 directly binds to LINE1 5'-UTR and the binding is enhanced in senescent cells. The enrichment of PAX5 at the 5'-UTR promotes cellular senescence and SASP by activating LINE1. We also demonstrate that the longevity gene SIRT6 suppresses PAX5 transcription by directly binding to the PAX5 promoter, and overexpressing PAX5 abrogates the suppressive effect of SIRT6 on stress-dependent cellular senescence. Our work suggests that PAX5 could serve as a potential target for drug development aiming to suppress LINE1 activation and treat senescence-associated diseases.


Asunto(s)
Senescencia Celular , Elementos de Nucleótido Esparcido Largo , Factor de Transcripción PAX5 , Humanos , Regiones no Traducidas 5'/genética , Regulación de la Expresión Génica , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Retroelementos/genética , Fenotipo Secretor Asociado a la Senescencia/genética
2.
Nucleic Acids Res ; 52(9): 5107-5120, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38554113

RESUMEN

Sirtuin 2 (SIRT2) regulates the maintenance of genome integrity by targeting pathways of DNA damage response and homologous recombination repair. However, whether and how SIRT2 promotes base excision repair (BER) remain to be determined. Here, we found that independent of its catalytic activity SIRT2 interacted with the critical glycosylase OGG1 to promote OGG1 recruitment to its own promoter upon oxidative stress, thereby enhancing OGG1 promoter activity and increasing BER efficiency. Further studies revealed that SIRT2 was phosphorylated on S46 and S53 by ATM/ATR upon oxidative stress, and SIRT2 phosphorylation enhanced the SIRT2-OGG1 interaction and mediated the stimulatory effect of SIRT2 on OGG1 promoter activity. We also characterized 37 cancer-derived SIRT2 mutants and found that 5 exhibited the loss of the stimulatory effects on OGG1 transcription. Together, our data reveal that SIRT2 acts as a tumor suppressor by promoting OGG1 transcription and increasing BER efficiency in an ATM/ATR-dependent manner.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , ADN Glicosilasas , Reparación del ADN , Sirtuina 2 , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Humanos , Sirtuina 2/metabolismo , Sirtuina 2/genética , ADN Glicosilasas/metabolismo , ADN Glicosilasas/genética , Fosforilación , Regiones Promotoras Genéticas , Estrés Oxidativo , Activación Transcripcional , Células HEK293 , Daño del ADN , Transcripción Genética , Línea Celular Tumoral , Reparación por Escisión
3.
Cancer Biol Ther ; 24(1): 2229958, 2023 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-37408176

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors with increasing incidence rates and high mortality rates. The currently available methods for treating HCC include surgery, radiotherapy or chemotherapy, but all of them have limitations. Therefore, developing novel therapeutic methods for HCC is in great need. Here, in this study, we found that tanshinone I, a small molecule compound, inhibited the proliferation of HCC cells in a dose-dependent manner. We also observed that Tanshinone I destabilized genomes by inhibiting both NHEJ and HR repair pathways, which are responsible for repairing DNA double strand breaks (DSBs). Mechanistically, this compound suppressed the expression of 53BP1, and the recruitment of RPA2 to DNA damage sites. Importantly, we demonstrated that combining Tanshinone I with radiotherapy exhibited better therapeutic potential for treating HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Roturas del ADN de Doble Cadena , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Reparación del ADN , ADN/metabolismo , ADN/uso terapéutico , Reparación del ADN por Unión de Extremidades , Reparación del ADN por Recombinación
4.
Aging Dis ; 13(4): 987-1004, 2022 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-35855336

RESUMEN

As the population ages, age-related neurodegenerative diseases have become a major challenge in health science. Currently, the pathology of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, is still not fully understood. Remarkably, emerging evidence indicates a role of genomic DNA damage and repair in various neurodegenerative disorders. Here, we summarized the current understanding of the function of DNA damage repair, especially base excision repair and double strand break repair pathways, in a variety of neurodegenerative diseases. We concluded that exacerbation of DNA lesions is found in almost all types of neurodegenerative diseases, whereas the activities of different DNA repair pathways demonstrate distinct trends, depending on disease type and even brain region. Specifically, key enzymes involved in base excision repair are likely impaired in Alzheimer's disease and amyotrophic lateral sclerosis but activated in Parkinson's disease, while nonhomologous end joining is likely downregulated in most types of neurodegenerative diseases. Hence, impairment of nonhomologous end joining is likely a common etiology for most neurodegenerative diseases, while defects in base excision repair are likely involved in the pathology of Alzheimer's disease and amyotrophic lateral sclerosis but are Parkinson's disease, based on current findings. Although there are still discrepancies and further studies are required to completely elucidate the exact roles of DNA repair in neurodegeneration, the current studies summarized here provide crucial insights into the pathology of neurodegenerative diseases and may reveal novel drug targets for corresponding neurodegenerative diseases.

5.
Cell Cycle ; 21(4): 379-391, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34985375

RESUMEN

Chrysin, a natural compound isolated from various plants, such as the blue passion flower (Passiflora caerulea L.), exhibits multiple pharmacological activities, such as antitumor, anti-inflammatory and antioxidant activities. Accumulating evidence shows that chrysin inhibits cancer cell growth by inducing apoptosis and regulating cell cycle arrest. However, whether chrysin is involved in regulating genomic stability and its underlying mechanisms in breast cancer cells have not been determined. Here, we demonstrated that chrysin impairs genomic stability in MCF-7 and BT474 cells, inhibits cell survival and enhances the sensitivity of MCF-7 cells to chemotherapeutic drugs. Further experiments revealed that chrysin impairs DNA double-strand break (DSB) repair, resulting in accumulation of DNA damage. Mechanistic studies showed that chrysin inhibits the recruitment of the key NHEJ factor 53BP1 and delays the recruitment of the HR factor RAD51. Thus, we elucidated novel regulatory mechanisms of chrysin in DSB repair and proposed that a combination of chrysin and chemotherapy has curative potential in breast cancers.


Asunto(s)
Neoplasias de la Mama , Roturas del ADN de Doble Cadena , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , ADN , Reparación del ADN por Unión de Extremidades , Reparación del ADN , Femenino , Flavonoides , Inestabilidad Genómica , Humanos
6.
Cell Cycle ; 19(22): 3115-3126, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33064975

RESUMEN

Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 µM DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer.


Asunto(s)
Neoplasias Endometriales/metabolismo , Flavonoides/farmacología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Reparación del ADN por Recombinación/efectos de los fármacos , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Roturas del ADN de Doble Cadena/efectos de la radiación , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Neoplasias Endometriales/patología , Femenino , Humanos , Recombinasa Rad51/metabolismo , Proteína de Replicación A/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Rayos X
7.
Proc Natl Acad Sci U S A ; 117(42): 26356-26365, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33020270

RESUMEN

Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Cromonas/farmacología , Morfolinas/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Animales , Roturas del ADN de Doble Cadena/efectos de los fármacos , Daño del ADN , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Quimioterapia Combinada/métodos , Técnicas de Sustitución del Gen , Recombinación Homóloga , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Desnudos , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Reparación del ADN por Recombinación/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Ageing Res Rev ; 64: 101154, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32977059

RESUMEN

DNA carries the genetic information that directs complex biological processes; thus, maintaining a stable genome is critical for individual growth and development and for human health. DNA repair is a fundamental and conserved mechanism responsible for mending damaged DNA and restoring genomic stability, while its deficiency is closely related to multiple human disorders. In recent years, remarkable progress has been made in the field of DNA repair and aging. Here, we will extensively discuss the relationship among DNA damage, DNA repair, aging and aging-associated diseases based on the latest research. In addition, the possible role of DNA repair in several potential rejuvenation strategies will be discussed. Finally, we will also review the emerging methods that may facilitate future research on DNA repair.


Asunto(s)
Envejecimiento , Reparación del ADN , Envejecimiento/genética , Daño del ADN , Reparación del ADN/genética , Inestabilidad Genómica , Humanos , Rejuvenecimiento
9.
Nucleic Acids Res ; 48(16): 9181-9194, 2020 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-32789493

RESUMEN

The NAD+-dependent deacetylase and mono-ADP-ribosyl transferase SIRT6 stabilizes the genome by promoting DNA double strand break repair, thereby acting as a tumor suppressor. However, whether SIRT6 regulates nucleotide excision repair (NER) remains unknown. Here, we showed that SIRT6 was recruited to sites of UV-induced DNA damage and stimulated the repair of UV-induced DNA damage. Mechanistic studies further indicated that SIRT6 interacted with DDB2, the major sensor initiating global genome NER (GG-NER), and that the interaction was enhanced upon UV irradiation. SIRT6 deacetylated DDB2 at two lysine residues, K35 and K77, upon UV stress and then promoted DDB2 ubiquitination and segregation from chromatin, thereby facilitating downstream signaling. In addition, we characterized several SIRT6 mutations derived from melanoma patients. These SIRT6 mutants ablated the stimulatory effect of SIRT6 on NER and destabilized the genome due to (i) partial loss of enzymatic activity (P27S or H50Y), (ii) a nonsense mutation (R150*) or (iii) high turnover rates (G134W). Overall, we demonstrate that SIRT6 promotes NER by deacetylating DDB2, thereby preventing the onset of melanomagenesis.


Asunto(s)
Carcinogénesis/genética , Daño del ADN/genética , Proteínas de Unión al ADN/genética , Melanoma/genética , Sirtuinas/genética , Carcinogénesis/efectos de la radiación , Cromatina/genética , Cromatina/efectos de la radiación , Daño del ADN/efectos de la radiación , Reparación del ADN/efectos de la radiación , Regulación de la Expresión Génica/efectos de la radiación , Células HeLa , Humanos , Melanoma/patología , Mutación/efectos de la radiación , Ubiquitinación/efectos de la radiación , Rayos Ultravioleta/efectos adversos
10.
FASEB J ; 34(8): 10966-10983, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32592217

RESUMEN

Uterine leiomyomas (ULM) are a major public health issue contributing to high morbidity and poor pregnancy outcomes. However, its molecular pathogenesis is poorly understood. HMGA2-ULM is the second major subtype of human ULM and associates with large sizes, fast-growth, and high percentages of estrogen receptor α (ERα). As altered ERα expression plays a distinct role in ULM growth, here, we investigate a regulatory mechanism driving ULM growth via HMGA2 and ERα. We reveal a positive correlation of HMGA2 with ERα protein and demonstrate that HMGA2 promotes ULM cells proliferation via ERα. In addition, autophagy pathway and p62/SQSTM1 (a selective autophagy receptor) are found to participate in the regulation of HMGA2 and ERα. Moreover, HMGA2 suppresses the transcription of p62 by binding to its promoter, meanwhile, p62 interacts with ERα, and inhibition of p62 increases ERα expression and enhances cell viability in ULM, suggesting a novel mechanism of the HMGA2-p62-ERα axis in ULM proliferation. Notably, rapamycin, a familiar autophagy agonist, reduces ERα levels and the proliferation ability of ULM cells. This study demonstrates a causal role of the HMGA2-p62-ERα axis in preventing autophagy and increasing ERα expression in HMGA2-ULM. Therefore, blocking HMGA2-p62-ERα axis and targeting autophagy pathway establish a roadmap toward HMGA2-ULM medical treatment.


Asunto(s)
Proliferación Celular/fisiología , Receptor alfa de Estrógeno/genética , Proteína HMGA2/genética , Leiomioma/genética , Proteína Sequestosoma-1/genética , Neoplasias Uterinas/genética , Adulto , Autofagia/fisiología , Supervivencia Celular/genética , Células Cultivadas , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células HEK293 , Humanos , Leiomioma/patología , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética , Transcripción Genética/genética , Neoplasias Uterinas/patología , Útero/patología
11.
Aging Cell ; 19(2): e13062, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31782607

RESUMEN

The decline in DNA repair capacity contributes to the age-associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age-associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose-derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17-25 years; old: 10 donors with ages ranging 50-59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double-strand break (DSB) repair pathways-nonhomologous end joining (NHEJ) and homologous recombination (HR)-between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age-associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.


Asunto(s)
Tejido Adiposo/citología , Envejecimiento/genética , Roturas del ADN de Doble Cadena , Reparación del ADN/fisiología , Células Madre/metabolismo , Adulto , Envejecimiento/metabolismo , Reparación del ADN por Unión de Extremidades , Humanos , Persona de Mediana Edad , Reparación del ADN por Recombinación , Células Madre/efectos de los fármacos , Células Madre/enzimología , Regulación hacia Arriba , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/metabolismo , Adulto Joven
12.
Nucleic Acids Res ; 47(16): 8563-8580, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31291457

RESUMEN

Creating access to DNA double-strand break (DSB) sites in the chromatin context is an essential step during the repair process, but much remains to be determined about its regulatory mechanisms. Here, using a novel reporter cassette for simultaneous detection of homologous recombination (HR) and nonhomologous end joining (NHEJ) at the same chromosomal site, we report that the efficiency of HR but not NHEJ negatively correlates with nucleosome density. We demonstrate that PARP1 is required for HR by modulating nucleosome density at damage sites. Mechanistic studies indicate that the ATPase domain of BRG1 and the ZnF domain of SIRT1 interact with poly-ADP ribose (PAR) in response to DNA damage, and are responsible for bringing the two factors to broken DNA ends. At DNA damage sites, BRG1 and SIRT1 physically interact, whereupon SIRT1 deacetylates BRG1 at lysine residues 1029 and 1033, stimulating its ATPase activity to remodel chromatin and promote HR.


Asunto(s)
ADN Helicasas/genética , ADN/genética , Proteínas Nucleares/genética , Nucleosomas/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , Reparación del ADN por Recombinación , Sirtuina 1/genética , Factores de Transcripción/genética , Sitios de Unión , Línea Celular , Línea Celular Tumoral , Cloroquina/farmacología , ADN/metabolismo , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , ADN Helicasas/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Genes Reporteros , Células HEK293 , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Nucleosomas/química , Nucleosomas/efectos de los fármacos , Fenantrenos/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli Adenosina Difosfato Ribosa/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Sirtuina 1/metabolismo , Factores de Transcripción/metabolismo
14.
Plant Biotechnol J ; 14(3): 849-60, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26228739

RESUMEN

Water deficiency is a critical environmental condition that is seriously reducing global plant production. Improved water-use efficiency (WUE) and drought tolerance are effective strategies to address this problem. In this study, PdEPF1, a member of the EPIDERMAL PATTERNING FACTOR (EPF) family, was isolated from the fast-growing poplar clone NE-19 [Populus nigra × (Populus deltoides × Populus nigra)]. Significantly, higher PdEPF1 levels were detected after induction by dehydration and abscisic acid. To explore the biological functions of PdEPF1, transgenic triploid white poplars (Populus tomentosa 'YiXianCiZhu B385') overexpressing PdEPF1 were constructed. PdEPF1 overexpression resulted in increased water deficit tolerance and greater WUE. We confirmed that the transgenic lines with greater instantaneous WUE had approximately 30% lower transpiration but equivalent CO2 assimilation. Lower transpiration was associated with a 28% reduction in abaxial stomatal density. PdEPF1 overexpression not only strongly enhanced WUE, but also greatly improved drought tolerance, as measured by the leaf relative water content and water potential, under limited water conditions. In addition, the growth of these oxPdEPF1 plants was less adversely affected by reduced water availability than plants with a higher stomatal density, indicating that plants with a low stomatal density may be well suited to grow in water-scarce environments. Taken together, our data suggest that PdEPF1 improves WUE and confers drought tolerance in poplar; thus, it could be used to breed drought-tolerant plants with increased production under conditions of water deficiency.


Asunto(s)
Adaptación Fisiológica , Sequías , Proteínas de Plantas/metabolismo , Estomas de Plantas/fisiología , Populus/fisiología , Agua , Adaptación Fisiológica/genética , Secuencia de Aminoácidos , Secuencia de Bases , Deshidratación , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Tamaño de los Órganos , Filogenia , Proteínas de Plantas/química , Estomas de Plantas/anatomía & histología , Estomas de Plantas/ultraestructura , Transpiración de Plantas/fisiología , Plantas Modificadas Genéticamente , Populus/genética , Populus/crecimiento & desarrollo , Estrés Fisiológico/genética
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