2020
DOI: 10.3390/ijms21020446
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Cell Cycle and DNA Repair Regulation in the Damage Response: Protein Phosphatases Take Over the Reins

Abstract: Cells are constantly suffering genotoxic stresses that affect the integrity of our genetic material. Genotoxic insults must be repaired to avoid the loss or inappropriate transmission of the genetic information, a situation that could lead to the appearance of developmental abnormalities and tumorigenesis. To combat this threat, eukaryotic cells have evolved a set of sophisticated molecular mechanisms that are collectively known as the DNA damage response (DDR). This surveillance system controls several aspect… Show more

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Cited by 75 publications
(62 citation statements)
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References 171 publications
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“…The normal cell cycle can be modulated by many different factors, thus leading to alterations in cell proliferation which represent important features of cancer cells. Usually, after a genome damage, a DNA damage response (DDR) occurs, followed by the activation of DNA damage checkpoints (G1 and G2 phases), wherein cell cycle is blocked, thus restraining chromosome segregation until the damage could be fixed, and DNA repair systems are stimulated [89,90].…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…The normal cell cycle can be modulated by many different factors, thus leading to alterations in cell proliferation which represent important features of cancer cells. Usually, after a genome damage, a DNA damage response (DDR) occurs, followed by the activation of DNA damage checkpoints (G1 and G2 phases), wherein cell cycle is blocked, thus restraining chromosome segregation until the damage could be fixed, and DNA repair systems are stimulated [89,90].…”
Section: Discussionmentioning
confidence: 99%
“…A loss of G1 checkpoint is a common feature of cancer cells and allows mutagenic replication of damaged templates and other replication defects: this failure makes cells more reliant upon the S and G2 checkpoints to prevent DNA damage-triggered cell death [91]. Also, G2/M checkpoint can fail due to the presence of unreplicated or damaged DNA [90]. Phosphorylation of H2AX at the serine residue (S139) represents one of the earliest events upon DNA double-strand breaks and is involved in DDR induction, delayed cell cycle progression and DNA repair, thus leading to cells recovering or death if damage is unrepairable [92].…”
Section: Discussionmentioning
confidence: 99%
“…Mutual interactions between the incident radiation and local chromatin architecture further modify the micro-and nanoarchitecture of the damage site and, in turn, the potential risk of damage misrepair (summarized in Table 1). Correct selection of the best repair pathway under given pancellular and site-specific conditions is therefore nontrivial and directly influences the fate of damaged cells [9,17]. Hence, we conclude this review with a brief discussion on the relationship between the physical parameters of the ionizing radiation, the chromatin architecture, and the formation mechanism of chromosomal aberrations, representing common precursors of cancer development.…”
Section: Incorrect Dsb Repair Formation Of Chromosomal Aberrations Amentioning
confidence: 99%
“…The cell cycle has long been accepted as the main DSB repair pathway-regulating factor since the demand for sister chromatids (i.e., repair templates) restricts HR to S/G2 phase ( Figure 1A,B). Although HR can utilize homologous chromosomes or repetitive sequences as alternative templates in some organisms (including mice [15]) or under specific circumstances [16], in mammals, the resection of DNA ends (necessary to initiate HR) is generally actively inhibited in G1 cells to prevent recombination via these potentially mutagenic mechanisms [17][18][19][20]. Hence, NHEJ has historically been considered the dominant repair pathway in human cells, while broken DNA end resection is considered the critical factor for determining the pathway of repair and signaling [21].…”
Section: Global Versus Local Dsb Repair Pathway Selection and Regulationmentioning
confidence: 99%
“…This will induce an increase in CDK inhibitors (CDKIs) level including p21 (WAF1/Cip1) ( Smith et al., 2010 ) leading to cell cycle arrest and activate the appropriate DNA repair process prior to moving on to the following phase of the cell cycle. In the case of irreversible damage, DDR will eventually initiate apoptosis of the cell ( Zhou and Elledge, 2000 ; Roos and Kaina, 2013 ; Campos and Clemente-Blanco, 2020 ).…”
Section: Introductionmentioning
confidence: 99%