Elsevier

DNA Repair

Volume 85, January 2020, 102702
DNA Repair

To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response

https://doi.org/10.1016/j.dnarep.2019.102702Get rights and content

Highlights

  • CDK2 is activated when DNA is damaged by internal or external genotoxic stresses and its activation is necessary for triggering DDR.

  • CDK2 inactivation directly results in DNA damage and activation of DDR.

  • Application of CDK2 inhibitors is a promising therapeutic strategy for cancer treatment.

Abstract

CDK2 (cyclin-dependent kinase 2), a member of the CDK family, has been shown to play a role in many cellular activities including cell cycle progression, apoptosis and senescence. Recently, accumulating evidence indicates that CDK2 is involved in DNA damage and DNA repair response (DDR). When DNA is damaged by internal or external genotoxic stresses, CDK2 activity is required for proper DNA repair in vivo and in vitro, whereas inactivation of CDK2 by siRNA techniques or by inhibitors could result in DNA damage and stimulate DDR. Hence, CDK2 seems to play dual roles in DNA damage and DDR. On one aspect, it is activated and stimulates DDR to repair DNA damage when DNA damage occurs; on the other hand, its inactivation directly leads to DNA damage and evokes DDR. Here, we describe the roles of CDK2 in DNA damage and DDR, and discuss the potential application of CDK2 inhibitors as anti-cancer agents.

Introduction

Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases that drive the cell cycle machinery [1]. Upon binding to their regulatory partners cyclins, CDKs can be activated and play critical roles in cell cycle transition and gene transcription [1,2]. For CDKs, the phosphorylation of serine 14/threonine 15 by the WEE1 and MYT1 kinases inhibits CDKs activation by preventing ATP binding; while the inhibitions are opposed by cell division cycle (CDC25) phosphatase, which dephosphorylates serine 14/threonine 15 to promote CDKs activity [3,4]. In the early G1 phase, CDK4 and CDK6 form active complexes with D- type cyclins to initiate the cell division cycle [1]. Subsequently, CDK2 is activated and is predominantly responsible for promoting the S and G2 phases [1,5,6]. Later, by combining with cyclin B, CDK1 is active and controls the progression into the G2 phase and mitosis [1,2].

Among CDKs, CDK2 is an essential regulator of the cell cycle progression. In the late G1 phase, the cyclin E/CDK2 complex completes RB phosphorylation and drives G1/S transition [1,5,6]. Subsequently, CDK2 regulates cellular events in the S phase including DNA replication and centrosome duplication by binding with cyclin A and targeting its substrates such as DNA replication licensing protein (CDC6) [1,5]. Moreover, CDK2 is involved in a variety of cellular activities, including cell recombination, differentiation, metabolism, chromatin remodeling, embryonic development, apoptosis as well as senescence and meiosis [[7], [8], [9], [10]]. In addition, altered CDK2 activity has been reported to influence human carcinogenesis [[11], [12], [13], [14], [15], [16]].

DNA damage occurs constantly in cells owing to exogenous and endogenous stresses, and cells have consequently evolved signaling network called DNA repair response (DDR) to delay the cell cycle and direct DNA repair [[17], [18], [19]]. DDR is essential for maintaining genomic integrity and accurately transmitting genetic information [17,18]. If the damage is repaired incorrectly or left unrepaired, DNA damage can give rise to genomic instability such as mutations, deletions amplifications and chromosomal translocations, which leads to various outcomes such as senescence, apoptosis or malignant transformation. Various intrinsic and extrinsic genotoxic stresses such as mutagenic chemicals, reactive oxygen species (ROS), ionizing radiation (IR) and unresolved intermediates of physiologic topoisomerase and nuclease reactions, lead to various DNA damages commonly known as single-strand breaks (SSBs), double-strand breaks (DSBs) and base lesions among others. DSBs are the most dangerous DNA lesions which may cause potentially lethal or oncogenic chromosomal aberrations [18]. The two major transduction pathways of DDR, PI3K-like kinases ataxia-telangiectasia mutated (ATM)−CHK2 and rad3-related (ATR)−CHK1, are activated to repair DNA damage [20]. Predominantly, ATM−CHK2 responds to DSBs while ATR−CHK1 is primarily activated by replication protein A (RPA)-coated SSBs [21,22]. Following CHK1 and/or CHK2 activation, a wide range of downstream effectors, such as p53, BRCA1/2 and RAD51 are activated via post-translational modifications including phosphorylation as well as ubiquitination. These processes may prevent further progression by arresting the cell cycle and initiating DNA repair mechanisms [23]. When the insult exceeds the repair capacity, the cellular death pathways are triggered. The accumulation of DNA damages in the cells results in genomic instability that ultimately leads to carcinogenesis. In addition, mutations in DDR-related genes, such as FANCD2, BRCA1, BRCA2 and ATM, often lead to syndromes associated with genomic instability [24,25]. However, as a positive guardian of genomic stability and anti-tumorigenesis, DDR is associated with several negative effects such as decreasing the sensitivity of chemotherapy and radiotherapy [26]. Therefore, DDR kinase inhibitors are proposed as therapeutic targets for cancer treatment [24,25,27]. Recently, DDR was found to regulate the host immune response as well as the intercommunication between DNA-damaged cells and their microenvironment [25,28,29]. Furthermore, DNA repair also regulates cellular metabolism in response to DNA damage in order to avoid further genomic instability [25,30,31].

Section snippets

CDK2 activation is essential for DDR induced by DNA-damaged stresses

To date, extensive investigations have been performed to determine the differential roles of CDK2 in DNA damage and DDR. On one hand, CDK2 is required for DNA damage repair induced by various factors such as mutagenic agents, irradiation or reactive oxygen. On the other hand, inactivation of CDK2 directly leads to the DNA damage and stimulates DDR (Fig. 1). Consequently, CDK2 seems to play different roles based on the cellular states. In this review, we would summarize the current knowledge

CDK2 deficiency leads to DNA damage and DDR activation

CDK2 is not only required for accurate and instant repair of DNA damage induced by internal and external genomic stresses as discussed above, its deficiency could directly lead to DNA damage following DDR activation (Fig. 2), which is the initial step of CDK2-involvement in DNA damage process.

In porcine oocytes, CDK2 activity is not essential for oocyte maturation. However, treatment of procine embryos with CDK2 inhibitor caused blastocyst DNA damage, leading to foci formation of DSBs marker

Discussion

Although CDK2 controls the G1/S transition and promotes DNA replication, CDK2 knockout mice are viable and develop normally with a reduced body size, suggesting that CDK2 might be dispensable and its roles in cell cycle progression may be compensated [106]. However, both male and female CDK2 knockout mice were sterile, indicating that CDK2 is required for gamete development and meiosis [107]. Currently, accumulating data indicate evidence that some cyclins and CDKs participate in DDR [16,23,37,

Conclusion

The roles of CDK2 in DNA damage and DDR are complex. The data reviewed above indicate that for CDK2, to control the occurrence of DNA damage and activate DDR in cells or to be controlled by DNA damage and then activate DDR is dependent on cellular context. Moreover, the upstream signals that direct CDK2 to decide whether to activate repair of DNA damage or to trigger apoptosis or senescence are not currently known. In addition, it is not clear whether CDK2 is involved in DDR-mediated crosstalk

Declaration of Competing Interest

The authors have declared that no competing interest exists.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81571440and81601874) and Foundation of Liaoning Educational Committee (No. LZDK201703 and JC2019031).

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