scholarly journals DNA Damage Response and Cell Cycle Regulation in Pluripotent Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1548
Author(s):  
Andy Chun Hang Chen ◽  
Qian Peng ◽  
Sze Wan Fong ◽  
Kai Chuen Lee ◽  
William Shu Biu Yeung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Genomic Stability ◽  
Great Promise ◽  
Cell Based Therapy ◽  
Damage Response

Pluripotent stem cells (PSCs) hold great promise in cell-based therapy because of their pluripotent property and the ability to proliferate indefinitely. Embryonic stem cells (ESCs) derived from inner cell mass (ICM) possess unique cell cycle control with shortened G1 phase. In addition, ESCs have high expression of homologous recombination (HR)-related proteins, which repair double-strand breaks (DSBs) through HR or the non-homologous end joining (NHEJ) pathway. On the other hand, the generation of induced pluripotent stem cells (iPSCs) by forced expression of transcription factors (Oct4, Sox2, Klf4, c-Myc) is accompanied by oxidative stress and DNA damage. The DNA repair mechanism of DSBs is therefore critical in determining the genomic stability and efficiency of iPSCs generation. Maintaining genomic stability in PSCs plays a pivotal role in the proliferation and pluripotency of PSCs. In terms of therapeutic application, genomic stability is the key to reducing the risks of cancer development due to abnormal cell replication. Over the years, we and other groups have identified important regulators of DNA damage response in PSCs, including FOXM1, SIRT1 and PUMA. They function through transcription regulation of downstream targets (P53, CDK1) that are involved in cell cycle regulations. Here, we review the fundamental links between the PSC-specific HR process and DNA damage response, with a focus on the roles of FOXM1 and SIRT1 on maintaining genomic integrity.

scholarly journals Deficient DNA Damage Response and Cell Cycle Checkpoints Lead to Accumulation of Point Mutations in Human Embryonic Stem Cells

Stem Cells ◽  
2012 ◽  
Vol 30 (9) ◽  
pp. 1901-1910 ◽  
Author(s):  
Nevila Hyka-Nouspikel ◽  
Joëlle Desmarais ◽  
Paul J. Gokhale ◽  
Mark Jones ◽  
Mark Meuth ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Dna Damage Response ◽  
Human Embryonic Stem Cells ◽  
Point Mutations ◽  
Embryonic Stem ◽  
Cell Cycle Checkpoints ◽  
Damage Response

scholarly journals Role of the circadian clock "Death-Loop" in the DNA damage response underpinning cancer treatment resistance

2022 ◽  
Author(s):  
Ninel Miriam Vainshelbaum ◽  
Kristine Salmina ◽  
Bogdan I Gerashchenko ◽  
Marija Lazovska ◽  
Pawel Zayakin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Circadian Clock ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Early Embryo ◽  
Mitotic Slippage ◽  
Damage Response ◽  
Telomere Regulation

The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of CC assessed by bioinformatics on 11 primary cancer datasets (rho=0.83; p<0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC "death loop", the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.

scholarly journals Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations

2016 ◽  
Vol 186 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Kalpana Mujoo ◽  
E. Brian Butler ◽  
Raj K. Pandita ◽  
Clayton R. Hunt ◽  
Tej K. Pandita
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pluripotent Stem Cells ◽  
Damage Response ◽  
Ionizing Radiations

Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells

2013 ◽  
Vol 6 (259) ◽  
pp. ra5-ra5 ◽  
Author(s):  
J. Carreras Puigvert ◽  
L. von Stechow ◽  
R. Siddappa ◽  
A. Pines ◽  
M. Bahjat ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Systems Biology ◽  
Embryonic Stem Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Damage Response

scholarly journals Distinct Regulatory Mechanisms and Functions for p53-Activated and p53-Repressed DNA Damage Response Genes in Embryonic Stem Cells

2012 ◽  
Vol 46 (1) ◽  
pp. 30-42 ◽  
Author(s):  
Mangmang Li ◽  
Yunlong He ◽  
Wendy Dubois ◽  
Xiaolin Wu ◽  
Jianxin Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Regulatory Mechanisms ◽  
Damage Response

scholarly journals Stemness factor Sall4 is required for DNA damage response in embryonic stem cells

2015 ◽  
Vol 208 (5) ◽  
pp. 513-520 ◽  
Author(s):  
Jianhua Xiong ◽  
Dilyana Todorova ◽  
Ning-Yuan Su ◽  
Jinchul Kim ◽  
Pei-Jen Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Ataxia Telangiectasia Mutated ◽  
Mouse Escs ◽  
Chromatin Remodeling Complex ◽  
Damage Response ◽  
Underlying Mechanisms

Mouse embryonic stem cells (ESCs) are genetically more stable than somatic cells, thereby preventing the passage of genomic abnormalities to their derivatives including germ cells. The underlying mechanisms, however, remain largely unclear. In this paper, we show that the stemness factor Sall4 is required for activating the critical Ataxia Telangiectasia Mutated (ATM)–dependent cellular responses to DNA double-stranded breaks (DSBs) in mouse ESCs and confer their resistance to DSB-induced cytotoxicity. Sall4 is rapidly mobilized to the sites of DSBs after DNA damage. Furthermore, Sall4 interacts with Rad50 and stabilizes the Mre11–Rad50–Nbs1 complex for the efficient recruitment and activation of ATM. Sall4 also interacts with Baf60a, a member of the SWI/SNF (switch/sucrose nonfermentable) ATP-dependent chromatin-remodeling complex, which is responsible for recruiting Sall4 to the site of DNA DSB damage. Our findings provide novel mechanisms to coordinate stemness of ESCs with DNA damage response, ensuring genomic stability during the expansion of ESCs.

scholarly journals Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies

2018 ◽  
Vol 10 ◽  
pp. 175883591878665 ◽  
Author(s):  
Anna Minchom ◽  
Caterina Aversa ◽  
Juanita Lopez
Keyword(s):  
Cell Cycle ◽  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Genomic Stability ◽  
Critical Determinant ◽  
Potential Biomarker ◽  
Damage Response

Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit – for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.

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