scholarly journals Biochemical analysis of deacetylase activity of rice sirtuin OsSRT1, a class IV member in plants

2021 ◽  
Author(s):  
Sanghamitra Dey ◽  
Nilabhra Mitra
Keyword(s):  
Dna Damage ◽  
Abiotic Stress ◽  
Biochemical Analysis ◽  
Histone Deacetylation ◽  
Repair Pathway ◽  
C Terminus ◽  
Damage Repair ◽  
Negative Effect ◽  
Class Iv

The role of plant sirtuins is slowly unwinding. There are only reports of H3K9Ac deacetylation by OsSRT1. This belongs to class IV sirtuin family with a longer C-terminus. Here C-terminus is required for ligand binding and catalysis. OsSRT1 can deacetylate the lys residues at the N terminal tail of both H3 and H4. It can also target the non-histone target, OsPARP1 playing a role in DNA damage repair pathway. Changes in the extent of different histone deacetylation by OsSRT1 is also related with different abiotic stress conditions. NAM and ADP-ribose has negative effect on OsSRT1 deacetylation.

scholarly journals CK2α/CSNK2A1 Induces Resistance to Doxorubicin Through SIRT6 Mediated Activation of the DNA Damage Repair Pathway

2021 ◽  
Author(s):  
Usama Khamis Hussein ◽  
Asmaa Gamal Ahmed ◽  
Yiping Song ◽  
See-Hyoung Park ◽  
Kyoung Min Kim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Dna Damage Repair ◽  
Repair Pathway ◽  
Osteosarcoma Cells ◽  
Cytotoxic Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin

Abstract BackgroundCK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to the conventional anti-cancer therapies.MethodsWe evaluated the expression of CSNK2A1 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and phosphorylation of SIRT6 on Ser338 on the resistance to the anti-cancer effects of doxorubicin. Results Higher expression of CSNK2A1 predicted shorter overall survival and relapse-free survival in both general osteosarcoma patients and sub-population of patients who received postoperative chemotherapies. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to cytotoxic effects of doxorubicin, and knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and induction of the DNA damage repair pathway molecules ATM and Chk2. CSNK2A1 and SIRT6 mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells in vitro. ConclusionsThis study demonstrates that the expression of CSNK2A1 might be used as a prognostic indicator of osteosarcoma. In addition, it suggests that CSNK2A1 induces resistance to doxorubicin through phosphorylation of SIRT6-mediated activation of the DNA damage repair pathway. Therefore, blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for the poor prognostic subgroup of osteosarcomas with high expression of CSNK2A1.

scholarly journals Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

2020 ◽  
Author(s):  
Zhongkai Zhang ◽  
Sang Hoon Ha ◽  
Young Jae Moon ◽  
Usama Khamis Hussein ◽  
Yiping Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Repair Pathway ◽  
Anticancer Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin ◽  
Apoptotic Effects

Abstract Background: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

scholarly journals Understanding the mechanism of monoADP ribosylation in OsSRT1 and its linkage to the DNA repair system under stress conditions

2021 ◽  
Author(s):  
Nilabhra Mitra ◽  
Sanghamitra Dey
Keyword(s):  
Dna Repair ◽  
Abiotic Stress ◽  
Stress Conditions ◽  
Repair System ◽  
Repair Pathway ◽  
Natural Plant ◽  
Plant Polyphenol ◽  
Negative Effect ◽  
Strong Activator

The role of sirtuins in plants are slowly unraveling. There are only reports of H3K9Ac deacetylation by OsSRT1. Here our studies shade light on its dual enzyme capability with preference for mono ADP ribosylation over deacetylation. OsSRT1 can specifically transfer the single ADP ribose group on its substrates in an enzymatic manner. This mono ADPr effect is not well known in plants, more so for deacetylases. The products of this reaction (NAM and ADP ribose) have immense negative effect on this enzyme suggesting a tighter regulation. Resveratrol, a natural plant polyphenol proves to be a strong activator of this enzyme at 150 μM concentration. Under different abiotic stress conditions, we could link this ADP ribosylase activity to the DNA repair pathway by activating the enzyme PARP1. Metal stress in plants also influences these enzyme activities.

scholarly journals Inhibition of SIRT6 Potentiates the Anti-Tumor Effect of Doxorubicin through Suppression of the DNA Damage Repair Pathway in Osteosarcoma

2020 ◽  
Author(s):  
Zhongkai Zhang ◽  
Sang Hoon Ha ◽  
Young Jae Moon ◽  
Usama Khamis Hussein ◽  
Yiping Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Repair Pathway ◽  
Anticancer Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin ◽  
Apoptotic Effects

Abstract Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

scholarly journals Role of Histone Methylation in Maintenance of Genome Integrity

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1000
Author(s):  
Arjamand Mushtaq ◽  
Ulfat Syed Mir ◽  
Clayton R. Hunt ◽  
Shruti Pandita ◽  
Wajahat W. Tantray ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Methylation ◽  
Genomic Stability ◽  
Genome Integrity ◽  
Repair Pathway ◽  
Post Translational Modifications ◽  
Damage Repair ◽  
Repair Protein ◽  
Cellular Pathways

: Packaging of the eukaryotic genome with histone and other proteins forms a chromatin structure that regulates the outcome of all DNA mediated processes. The cellular pathways that ensure genomic stability detect and repair DNA damage through mechanisms that are critically dependent upon chromatin structures established by histones and, particularly upon transient histone post-translational modifications. Though subjected to a range of modifications, histone methylation is especially crucial for DNA damage repair, as the methylated histones often form platforms for subsequent repair protein binding at damaged sites. In this review, we highlight and discuss how histone methylation impacts the maintenance of genome integrity through effects related to DNA repair and repair pathway choice.

scholarly journals Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Zhongkai Zhang ◽  
Sang Hoon Ha ◽  
Young Jae Moon ◽  
Usama Khamis Hussein ◽  
Yiping Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Repair Pathway ◽  
Anticancer Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin ◽  
Apoptotic Effects

Abstract Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

scholarly journals CK2α/CSNK2A1 Induces Resistance to Doxorubicin through SIRT6-Mediated Activation of the DNA Damage Repair Pathway

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1770
Author(s):  
Usama Khamis Hussein ◽  
Asmaa Gamal Ahmed ◽  
Yiping Song ◽  
Kyoung Min Kim ◽  
Young Jae Moon ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Dna Damage Repair ◽  
Repair Pathway ◽  
Osteosarcoma Cells ◽  
Cytotoxic Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin

CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.

scholarly journals LINC-PINT impedes DNA repair and enhances radiotherapeutic response by targeting DNA-PKcs in nasopharyngeal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
You-hong Wang ◽  
Zhen Guo ◽  
Liang An ◽  
Yong Zhou ◽  
Heng Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Cancer ◽  
Noncoding Rnas ◽  
Dependent Protein Kinase ◽  
Damage Repair ◽  
Dependent Protein ◽  
Cancer Tissues

AbstractRadioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

scholarly journals PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

2021 ◽  
Vol 22 (10) ◽  
pp. 5112
Author(s):  
Lotte van Beek ◽  
Éilís McClay ◽  
Saleha Patel ◽  
Marianne Schimpl ◽  
Laura Spagnolo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Parp Inhibitors ◽  
Covalent Modification ◽  
Activation Mechanism ◽  
Cancer Therapies ◽  
Damage Repair ◽  
Complementary Role ◽  
Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

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