Homologous Recombination Conserves DNA Sequence Integrity Throughout the Cell Cycle in Embryonic Stem Cells

Serrano, Lourdes; Liang, Li; Chang, Yi-Ming; Deng, Li; Maulion, Christopher; Nguyen, Son C.; Tischfield, Jay A.

doi:10.1089/scd.2010.0159

Cited by 65 publications

(67 citation statements)

References 58 publications

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“…We performed a quantitative analysis of the spatial and cell cycle distribution of γH2AX foci in exponentially growing primary mouse fibroblasts (Fig 4C and D). Sites of active DNA replication during S‐phase progression were identified by the incorporation of EdU, and G1 and G2 cells were segmented according to their nuclear volume based on DAPI staining of 3D‐reconstructed individual nuclei (Serrano et al , 2011) (Appendix Fig S4A). We found a higher number of γH2AX foci throughout the cell cycle in SIRT7‐deficient than in WT cells (Fig 4C and D, NoIR).…”

Section: Resultsmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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Section: Resultsmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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“…In addition to active DNA damage repair mechanisms, faithful DNA replication is essential for maintaining genomic integrity in the normal cell cycle. In asynchronous, exponentially growing cells, up to 60% of mouse ESCs (mESCs) were in S phase, compared with 20% of mouse embryonic fibroblasts (MEFs) [5][6][7][8]. Obstacles on the DNA template, caused by exogenous or endogenous factors, such as ultraviolet light, reactive oxygen species, nutrient deficiency, and deregulation of replication activity, frequently impede replication fork progression, which can result in replication fork collapse and the formation of replicationdependent DNA double-strand breaks (DSBs) [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Failed DSB repair or inaccurate DNA repair causes chromosomal rearrangement, chromosome loss, or carcinogenesis [13,14]. In mESCs, DSBs are predominantly repaired through the high-fidelity HR pathway, which occurs throughout the cell cycle [6,15]. The essential role of HR in mESCs is supported by the fact that basal levels of proteins involved in HR are higher in mESCs than in fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Rad51 Regulates Cell Cycle Progression by Preserving G2/M Transition in Mouse Embryonic Stem Cells

Yoon

Kim

et al. 2014

Stem Cells and Development

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Homologous recombination (HR) maintains genomic integrity against DNA replication stress and deleterious lesions, such as double-strand breaks (DSBs). Rad51 recombinase is critical for HR events that mediate the exchange of genetic information between parental chromosomes in eukaryotes. Additionally, Rad51 and HR accessory factors may facilitate replication fork progression by preventing replication fork collapse and repair DSBs that spontaneously arise during the normal cell cycle. In this study, we demonstrated a novel role for Rad51 during the cell cycle in mouse embryonic stem cells (mESCs). In mESCs, Rad51 was constitutively expressed throughout the cell cycle, and the formation of Rad51 foci increased as the cells entered S phase. Suppression of Rad51 expression caused cells to accumulate at G2/M phase and activated the DNA damage checkpoint, but it did not affect the self-renewal or differentiation capacity of mESCs. Even though Rad51 suppression significantly inhibited the proliferation rate of mESCs, Rad51 suppression did not affect the replication fork progression and speed, indicating that Rad51 repaired DNA damage and promoted DNA replication in S phase through an independent mechanism. In conclusion, Rad51 may contribute to G2/M transition in mESCs, while preserving genomic integrity in global organization of DNA replication fork.

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“…Embryonic cells, however, are programmed to operate under the restricted timeframe of early gestation, and damagedirected cell cycle arrest is not a viable option, as this would greatly reduce the chances for embryo survival. Mutagenesis is actively suppressed in embryonic cells compared to same-species somatic cells, sometimes in orders of magnitude [84,85]. All this leaves out only one logical option -apoptosis of the damaged embryonic cells, in the hope that the intact cells may replenish the population.…”

Section: Signalling Mediated By Erk1/2mentioning

confidence: 99%

Of mice and men – differential mechanisms of maintaining the undifferentiated state in mESC and hESC

Arabadjiev¹,

Petkova²,

Momchilova³

et al. 2012

Biodiscovery

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Homologous Recombination Conserves DNA Sequence Integrity Throughout the Cell Cycle in Embryonic Stem Cells

Cited by 65 publications

References 58 publications

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

Rad51 Regulates Cell Cycle Progression by Preserving G2/M Transition in Mouse Embryonic Stem Cells

Of mice and men – differential mechanisms of maintaining the undifferentiated state in mESC and hESC

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