Twists and turns in the function of DNA damage signaling and repair proteins by post-translational modifications

DNA Repair ◽  
2007 ◽  
Vol 6 (5) ◽  
pp. 561-577 ◽  
Author(s):  
Ugo Déry ◽  
Jean-Yves Masson
Keyword(s):  
Dna Damage ◽  
Post Translational Modifications ◽  
Dna Damage Signaling

scholarly journals Molecular Mechanism of Nuclear Tau Accumulation and its Role in Protein Synthesis

2020 ◽  
Author(s):  
Miguel Portillo ◽  
Ekaterina Eremenko ◽  
Shai Kaluski ◽  
Lior Onn ◽  
Daniel Stein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Protein Synthesis ◽  
Energy Production ◽  
Protein Translation ◽  
Nuclear Accumulation ◽  
Rrna Synthesis ◽  
Global Changes ◽  
Post Translational Modifications ◽  
Dna Damage Signaling

AbstractSeveral neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Tau-K174Q expressing cells showed changes in the nucleolus increasing their intensity and number, as well as in rRNA synthesis leading to an increase in protein translation and ATP reduction. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.

scholarly journals The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability

2021 ◽  
Vol 22 (6) ◽  
pp. 2976
Author(s):  
Amira Fitieh ◽  
Andrew J. Locke ◽  
Mobina Motamedi ◽  
Ismail Hassan Ismail
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Gene Silencing ◽  
Strand Break ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Post Translational Modifications ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Group Protein

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.

scholarly journals Collateral Victim or Rescue Worker?—The Role of Histone Methyltransferases in DNA Damage Repair and Their Targeting for Therapeutic Opportunities in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Lishu He ◽  
Gwen Lomberk
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Cancer Therapeutics ◽  
Great Promise ◽  
Cell Integrity ◽  
Post Translational Modifications ◽  
Dna Damage Signaling ◽  
Damage Repair ◽  
Chromatin Biology

Disrupted DNA damage signaling greatly threatens cell integrity and plays significant roles in cancer. With recent advances in understanding the human genome and gene regulation in the context of DNA damage, chromatin biology, specifically biology of histone post-translational modifications (PTMs), has emerged as a popular field of study with great promise for cancer therapeutics. Here, we discuss how key histone methylation pathways contribute to DNA damage repair and impact tumorigenesis within this context, as well as the potential for their targeting as part of therapeutic strategies in cancer.

scholarly journals PRL3 induces polypoid giant cancer cells eliminated by PRL3-zumab to reduce tumor relapse

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Min Thura ◽  
Zu Ye ◽  
Abdul Qader Al-Aidaroos ◽  
Qiancheng Xiong ◽  
Jun Yi Ong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Cancer Cells ◽  
Embryonic Stem ◽  
Genotoxic Stress ◽  
Stem Cell Markers ◽  
Tumor Removal ◽  
Primary Tumors ◽  
Tumor Relapse ◽  
Dna Damage Signaling

AbstractPRL3, a unique oncotarget, is specifically overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. Herein, firstly, we show that PRL3 induces Polyploid Giant Cancer Cells (PGCCs) formation. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. The correlations between PRL3 overexpression and PGCCs attributes raised possibilities that PRL3 could be involved in PGCCs formation. Secondly, we show that PRL3+ PGCCs co-express the embryonic stem cell markers SOX2 and OCT4 and arise mainly due to incomplete cytokinesis despite extensive DNA damage. Thirdly, we reveal that PRL3+ PGCCs tolerate prolonged chemotherapy-induced genotoxic stress via suppression of the pro-apoptotic ATM DNA damage-signaling pathway. Fourthly, we demonstrated PRL3-zumab, a First-in-Class humanized antibody drug against PRL3 oncotarget, could reduce tumor relapse in ‘tumor removal’ animal model. Finally, we confirmed that PGCCs were enriched in relapse tumors versus primary tumors. PRL3-zumab has been approved for Phase 2 clinical trials in Singapore, US, and China to block all solid tumors. This study further showed PRL3-zumab could potentially serve an ‘Adjuvant Immunotherapy’ after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse.

scholarly journals Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maya Spichal ◽  
Bree Heestand ◽  
Katherine Kretovich Billmyre ◽  
Stephen Frenk ◽  
Craig C. Mello ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Environmental Restoration ◽  
Related Gene ◽  
C Elegans ◽  
Dna Damage Signaling ◽  
Multiple Phenotypes ◽  
Granule Structure ◽  
Germ Granules ◽  
Late Generation

AbstractIn several species, Piwi/piRNA genome silencing defects cause immediate sterility that correlates with transposon expression and transposon-induced genomic instability. In C. elegans, mutations in the Piwi-related gene (prg-1) and other piRNA deficient mutants cause a transgenerational decline in fertility over a period of several generations. Here we show that the sterility of late generation piRNA mutants correlates poorly with increases in DNA damage signaling. Instead, sterile individuals consistently exhibit altered perinuclear germ granules. We show that disruption of germ granules does not activate transposon expression but induces multiple phenotypes found in sterile prg-1 pathway mutants. Furthermore, loss of the germ granule component pgl-1 enhances prg-1 mutant infertility. Environmental restoration of germ granule function for sterile pgl-1 mutants restores their fertility. We propose that Piwi mutant sterility is a reproductive arrest phenotype that is characterized by perturbed germ granule structure and is phenocopied by germ granule dysfunction, independent of genomic instability.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

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