Maintenance of genome integrity and active homologous recombination in embryonic stem cells

Abstract

Embryonic stem cells (ESCs) possess specific gene expression patterns that confer the ability to proliferate indefinitely and enable pluripotency, which allows ESCs to differentiate into diverse cell types in response to developmental signals. Compared to differentiated cells, ESCs harbor an elevated level of homologous recombination (HR)-related proteins and exhibit exceptional cell cycle control, characterized by a high proliferation rate and a prolonged S phase. HR is involved in several aspects of chromosome maintenance. For instance, HR repairs impaired chromosomes and prevents the collapse of DNA replication forks during cell proliferation. Thus, HR is essential for the maintenance of genomic integrity and prevents cellular dysregulation and lethal events. In addition, abundant HR proteins in the prolonged S phase can efficiently protect ESCs from external damages and protect against genomic instability caused by DNA breaks, facilitating rapid and accurate DNA break repair following chromosome duplication. The maintenance of genome integrity is key to preserving the functions of ESCs and reducing the risks of cancer development, cell cycle arrest, and abnormal replication. Here, we review the fundamental links between the stem cell-specific HR process and DNA damage response as well as the different strategies employed by ESCs to maintain genomic integrity.

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

“…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]. However, notably, embryonic stem cells are essentially dependent on HR [22][23][24], and HR templated by homologous chromosomes is the predominant repair pathway throughout the cell cycle in these cells in mice [25]. The activity of NHEJ and HR thus evidently depends on additional factors uniformly affecting the cell nucleus (herein referred to as "global factors") ( Figure 1B).…”

DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?

“… 12 Efficiency of the DSB repair is achieved due to the active homologous recombination in ESCs. 16 The activity of caspases increases during the differentiation of the ESCs. 17 It was hypothesized that the transient increase of the caspase activity with the following activation of the caspase-dependent DNAse is necessary for stem cell differentiation.…”

A Tale of Two States: Pluripotency Regulation of Telomeres

“…However, the selfrenewal and high proliferative capacities expose mESCs to high levels of DNA replication stress (Ahuja et al, 2016). Critically, mutations acquired during early stages of embryonic development must be promptly repaired to prevent chromosomal defects, infertility, or embryonic lethality (Choi et al, 2020). mESCs exploit distinct molecular and biological signatures, like higher proliferative rates, unique cell-cycle composition and checkpoints and better competence for genomic stability maintenance (Boheler, 2009;Boroviak et al, 2015;Ahuja et al, 2016;Vitale et al, 2017).…”

“…Due to the relatively short G1 phase, mESCs are unable to complete DDR before moving to the S-phase (Hyka-Nouspikel et al, 2012;Choi et al, 2017), leading to accumulation of ssDNA gaps and formation of DSBs at stalled replication forks and to accumulation of γH2AX (Chuykin et al, 2008;Banáth et al, 2009;Choi et al, 2020;Blakemore et al, n.d.). Despite rapid proliferation rates and elevated replication stress (Banáth et al, 2009;Ahuja et al, 2016), mESCs have surprisingly low mutation rates.…”