Role of Histone Methylation in Maintenance of Genome Integrity

Packaging of the eukaryotic DNA 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 which are critically dependent upon chromatin structures established by histones and, particularly, transient histone post-translational modifications . Though subject 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.

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The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

Cellular Signalling ◽

10.1016/j.cellsig.2017.07.019 ◽

2017 ◽

Vol 39 ◽

pp. 18-31 ◽

Cited By ~ 10

Author(s):

Somsubhra Nath ◽

Shrabasti Roychoudhury ◽

Matthew J. Kling ◽

Heyu Song ◽

Pranjal Biswas ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Protein

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

10.21203/rs.3.rs-624074/v1 ◽

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.

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

10.21203/rs.3.rs-53497/v2 ◽

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.

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Post-translational modifications of lysine in DNA-damage repair

Essays in Biochemistry ◽

10.1042/bse0520093 ◽

2012 ◽

Vol 52 ◽

pp. 93-111 ◽

Cited By ~ 13

Author(s):

Snehajyoti Chatterjee ◽

Parijat Senapati ◽

Tapas K. Kundu

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Post Translational Modifications ◽

Dna Repair Mechanisms ◽

The Past ◽

Damage Repair ◽

Lysine Residues ◽

Repair Mechanisms ◽

Genotoxic Insult

DNA damage in cells is often the result of constant genotoxic insult. Nevertheless, efficient DNA repair pathways are able to maintain genomic integrity. Over the past decade it has been revealed that it is not only kinase signalling pathways which play a central role in this process, but also the different post-translational modifications at lysine residues of histone (chromatin) and non-histone proteins. These lysine modifications include acetylation, methylation, ubiquitination and SUMOylation. Genomic instability is often the major cause of different diseases, especially cancer, where lysine modifications are altered and thereby have an impact on the various DNA repair mechanisms. This chapter will discuss the recent advances in our understanding of the role of different lysine modifications in DNA repair and its physiological consequences.

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TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells

Nature Communications ◽

10.1038/s41467-019-12126-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Jiajing Chen ◽

Zikang Wang ◽

Xudong Guo ◽

Fudong Li ◽

Qingtao Wei ◽

...

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Embryonic Stem Cells ◽

Critical Role ◽

Embryonic Stem ◽

Genomic Stability ◽

Vital Role ◽

Damage Repair ◽

The Relationship

Abstract Recognition of specific chromatin modifications by distinct structural domains within “reader” proteins plays a critical role in the maintenance of genomic stability. However, the specific mechanisms involved in this process remain unclear. Here we report that the PHD-Bromo tandem domain of tripartite motif-containing 66 (TRIM66) recognizes the unmodified H3R2-H3K4 and acetylated H3K56. The aberrant deletion of Trim66 results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). Moreover, we find that the recognition of histone modification by TRIM66 is critical for DNA damage repair (DDR) in ESCs. TRIM66 recruits Sirt6 to deacetylate H3K56ac, negatively regulating the level of H3K56ac and facilitating the initiation of DDR. Importantly, Trim66-deficient blastocysts also exhibit higher levels of H3K56ac and DNA damage. Collectively, the present findings indicate the vital role of TRIM66 in DDR in ESCs, establishing the relationship between histone readers and maintenance of genomic stability.

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1546P Prognostic role of tumoral DNA damage repair protein expression in patients with resectable pancreatic cancer

Annals of Oncology ◽

10.1016/j.annonc.2020.08.2029 ◽

2020 ◽

Vol 31 ◽

pp. S947

Author(s):

F. Ceylan ◽

D.C. Guven ◽

H. Taban ◽

O. Aktepe ◽

S. Kilickap ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Protein Expression ◽

Dna Damage Repair ◽

Prognostic Role ◽

Resectable Pancreatic Cancer ◽

Damage Repair ◽

Repair Protein

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

10.21203/rs.3.rs-53497/v1 ◽

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.

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

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01759-9 ◽

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.

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

10.1101/2021.11.05.467508 ◽

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.

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