Daughters sense their mother's stress

The human genome is constantly challenged by genotoxic stress arising from endogenous and exogenous sources, which interferes with proper DNA replication. To counteract such replication stress and protect genome integrity, cells employ a complex DNA damage response (DDR) machinery that encompasses repair pathways to fix different types of DNA damage, and cell cycle checkpoints to provide the time needed to repair DNA lesions [1]. However, unresolved DNA lesions and DNA replication intermediates can persist and be transmitted into the subsequent G1 phase of daughter cells, where they are shielded by the p53-binding protein 1 (53BP1) as nuclear bodies [2]. Consequently, replication stress induced e.g. by genotoxic agents or inhibition of Ataxia telangiectasia and Rad3 related (ATR) kinase increases the number of 53BP1 bodies per cell as well as the subset of cells carrying 53BP1-marked lesions.

In this issue of Cell Cycle, Lezaja and Altmeyer elaborate on this concept and link the level of replication stress-induced DNA lesions by inhibition of ATR to the fate of daughter cells [3]. Using 53BP1 and cell-cycle reporter cell lines in time lapse experiments, they find that increasing the number of G1-transmitted DNA lesions leads either to extended quiescence with unresolved 53BP1 bodies or a delay in S-phase entry upon which 53BP1 bodies resolve. Interestingly, DNA damage-induced quiescence and delay in S-phase commitment depend on tumor suppressor p53, as cells without functional p53 abrogated the replication stress-induced prolonged G1 phase. Instead, p53-negative cells enter S phase nearly normally, but with unresolved DNA lesions. This is a critical finding, because p53 is a central part of the DDR barrier that is frequently mutated in human cancers [4]. Generally, p53 delays the G1/S transition by directly driving the expression of p21 (CDKN1A), an inhibitor of cell-cycle-promoting CDK kinases.

Consistently with such concept, Spencer et al. reported that two populations of cells exist after mitosis: one that rapidly commits to S phase, and one that enters a transient state of quiescence [5]. This study furthermore showed that quiescence depends on the presence of p21, which itself is subject to regulation by mitogens before mitosis [5]. Moreover, a complementary recent work demonstrated that activation of p53 before mitosis is a critical step for DNA damage-induced quiescence in daughter cells. The half-live of p53 increases to over 7 hours in the presence of DNA damage, ensuring transfer of p53 activity into and de novo expression of p21 in daughter cells [6]. Notably, the anti-proliferative function of p21 in daughter cells thereby competes with the mitogen-driven expression of pro-proliferative cyclin D1. This leads to a scenario, where access to increasing amounts of serum and epidermal growth factor (EGF) can counteract DNA damage-induced quiescence. The underlying mechanism for this phenomenon is likely a raising threshold of p21 abundance that is needed to block S-phase entry, as cells that escaped quiescence showed a higher cyclin D1/p21 ratio. Supporting data come also from a study which recently showed that p21 levels and a subsequent proliferation-quiescence decision correlate with DNA lesions in daughter cells in the presence of mitogens [7]. Here, cells with low and intermediate p21 levels in G1 can enter S phase, while cells with high p21 levels remain in quiescence and harbour unresolved DNA lesions.

Similar to observations by the Altmeyer laboratory [3], Arora et al. also just described three major daughter cell populations that enter the next cell cycle with different kinetics. By combining CDK2 activity with 53BP1 reporter cells, they correlate the amount of DNA lesions transmitted through mitosis to the cell cycle behavior in daughter cells by categorizing into: i) proliferating (low amount of 53BP1 bodies), ii) quiescent to proliferating (moderate amount of 53BP1 bodies), and iii) quiescent (high amount of 53BP1 bodies) cell populations [8]. Interestingly, they also found that cells of the ‘quiescent-to-proliferative’ population, which show delayed S-phase entry, can pass the decision to postpone proliferation onto subsequent cell cycles.

Collectively, the data put forward by Lezaja and Altmeyer and the complementary studies discussed here, show that replication stress in mother cells has impact on cell cycle kinetics of their daughters, if unrepaired DNA lesions get passed on through mitosis. A cell-to-cell heterogeneity in cell-cycle lengths within cell cultures had been noticed for a long time and these studies now shed new light on basic cell cycle control. Ultimately, a model emerges, where the previous S phase can be seen as the beginning of the cell cycle, ending with the following G1 of daughter cells as a read-out to enforce cell fate decisions based on the cellular fitness (Figure 1).

Figure 1.

Replication stress in S phase of mother cells can cause DNA lesions that will be transmitted through mitosis. Depending on the amount of inherited DNA lesions and corresponding levels of p21, p53 positive daughter cells show three subpopulations: proliferative (green), delayed (yellow), quiescent (red). If p53 is absent, daughter cells with inherited DNA lesions can enter S phase without delay.

While this exciting concept promises to advance our understanding of cell cycle regulation, these reports also raise a host of questions and may inspire new directions of research. The parallels between p53's roles in the replication stress-induced DDR anti-tumor barrier [4] and DNA damage-induced quiescence point to shared impacts of oncogenes and mitogens in cell-fate decisions. But what is the longer-term fate of such quiescent cells, and their potential for senescence, cell death or malignant transformation? Can such cell-fate decisions be safely manipulated pharmacologically? Indeed, the findings discussed here have broader implications for research on organismal development, aging and aging-related pathologies including cancer.

Funding Statement

Kræftens Bekæmpelses Videnskabelige Udvalg (KBVU) [R40-A2030], Novo Nordisk Foundation [NNF15OC0016584].

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.