Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101559


 CDS1;  CHK2;  RAD53

Historical Background

Every day, each cell of our body is subjected to up to 1 million DNA lesions. These alterations are induced by genotoxic agents (e.g., chemicals, radiations), harmful metabolites, or DNA replication mistakes.

To prevent the replication of cells with damaged DNA, all organisms have evolved repair mechanisms that, in eukaryotes, are called the DNA-damage response (DDR). DDR is a network of molecular pathways that detect DNA lesions and, depending on the severity, arrest the cell cycle at checkpoints, repair DNA or, in presence of irreparable damage, initiate a program of permanent duplication arrest (senescence) or cellular suicide (apoptosis) (Ciccia and Elledge 2010).

In human cells, the activation of the DDR (Fig. 1) is promoted when sensor proteins find structural distortions or breaks on the DNA and attract to these sites the serine/threonine-protein kinase ATM (also called ataxia-telangiectasia mutated) and the serine/threonine-protein kinase ATR (also called ataxia telangiectasia and Rad3-related protein). These proteins belong to the phosphatidylinositol-3 kinase (PI3K) family and are the apical kinases of the DDR cascade, but while ATM is mainly activated by DNA double-strand breaks (DSBs), ATR is primarily implicated in the response to stalled replication forks or UV-induced pyrimidine dimers. Upon DNA damage, ATM and ATR directly phosphorylate numerous substrates to start the appropriate cellular response and, cooperating with the checkpoint mediators and the transducer kinases, they spread the DNA-damage signal. Whereas the checkpoint mediators (MDC1, 53BP1, and BRCA1 for ATM; and TopBP1 and claspin for ATR) contribute to the activation of ATM and ATR by indirectly binding to the lesions and facilitating the recruitment of DDR factors to the damaged sites, the transducer kinases (CHK1 for ATR and CHK2 for ATM) are involved in DNA-damage signal transduction through a phosphorylation cascade. Indeed these kinases, by targeting effector proteins, which are the final executors of DDR functions, enhance or redirect the ATM/ATR-mediated response.
CHEK2, Fig. 1

The DNA-damage response in human cells. In presence of DNA lesions, sensor proteins attract to damaged sites the apical kinases ATM, ATR, and DNA-PK which, in turn, transduce the damage signal to the transducer kinases and to effector proteins, finally inducing the appropriate cellular response

Initially discovered in 1998, human CHK2 protein, encoded by CHEK2 gene, is the mammalian homolog of S. cerevisiae Rad53 and S. pombe Cds1 kinases that are active in yeast DDR, and it is conserved also in mouse, rat, zebrafish, X. laevis, D. melanogaster, and C. Elegans (Matsuoka et al. 1998). CHK2 was then confirmed to be implicated in the human response to DNA lesions, and its mechanism of activation has been clarified in 2002. In addition, CHK2 was proven to be a low-penetrance cancer susceptibility gene, as CHEK2 mutations have been found in cancer patients since 1999.

As many other components of the DDR, CHK2 is involved in other crucial cellular pathways that require maintenance or restoration of genome integrity (Fig. 2) (Zannini et al. 2014), such as the control of mitosis and meiosis progression and the maintenance of stem cell genomic stability. Moreover, CHK2 has been implicated in the response to viral infections and to mitochondrial DNA damage. In addition, it has been found that CHK2 regulates circadian proteins which in turn regulate CHK2 itself.
CHEK2, Fig. 2

Overview of CHK2’s activities. Scheme of CHK2 functions in DDR and normal cellular physiology

Mechanisms of CHK2 Activation and Inactivation

Human CHK2 is a 65-KDa protein composed of 543 residues and characterized by three distinct functional domains (Zannini et al. 2014). At the N-terminus, spanning amino acids 19–69, there is a region called SQ/TQ cluster domain (SCD) rich in serine-glutamine and threonine-glutamine pairs, which are targets of PI3K family kinases (including ATM and ATR). Between residues 112 and 175, there is a forkhead-associated (FHA) domain responsible for the association of CHK2 with phosphorylated proteins. At the C-terminus, a canonical kinase domain spans residues 220–486 and comprises a T-loop region (residues 366-406) that undergoes autophosphorylation to guarantee efficient kinase activity.

During normal cell growth, CHK2 is an inactive nuclear monomer. After DNA damage, CHK2, phosphorylated by ATM on T68 and on other residues in the SCD region, undergoes a conformational change that promotes CHK2 dimerization through the binding of the FHA domain of one monomer with the phosphorylated SCD region of another (Ahn et al. 2002). CHK2 dimers can then autophosphorylate at residues S260 and T432 of the kinase domain, at T383 and T387 in the T-loop, and at S516, thus promoting conformational changes which finally lead to the dissociation of CHK2 dimers into fully active monomers (Fig. 3).
CHEK2, Fig. 3

CHK2 activation and inactivation. In unstressed cells, CHK2 exists as inactive monomers. Upon DNA damage, ATM phosphorylates CHK2 in the SQ/TQ rich region, promoting its dimerization and autophosphorylation. Successively, CHK2 dimers dissociate into active monomers

Beside ATM, other proteins are known to be involved in CHK2 activation (Zannini et al. 2014). Indeed, DNA-dependent protein kinase DNA-PKcs, another member of the PI3K family, phosphorylates exogenous CHK2 in undamaged BJ-hTERT human fibroblast cells and, after DNA damage, it was reported to phosphorylate a fraction of CHK2 molecules (Fig. 1) bound to chromatin or centrosomes. In addition, in response to DNA damage, Polo-like kinase-3 (PLK3) phosphorylates CHK2 at S62 (in the SCD) and at S73, whereas the DNA mismatch repair protein MSH2 associates with CHK2 at sites of damage. These events facilitate T68 phosphorylation by ATM promoting CHK2 activation. Also, the tumor suppressor protein PML, which is involved in acute promyelocytic leukemia and is the main component of PML-nuclear bodies (PML-NBs), seems to regulate CHK2 autophosphorylation. Inactive CHK2 partially localizes at PML-NBs, but, once activated, leaves these structures. A small fraction of CHK2 retained in PML-NBs phosphorylates PML and binds to p53, thus regulating PML-NBs number and PML-dependent apoptosis. Most recently, also DBC1, the negative regulator of SIRT1 deacetylase, was shown to be required for full Chk2 activation (Magni et al. 2015).

Differently from the activation, the mechanisms responsible for CHK2 inactivation are still not completely understood (Zannini et al. 2014). Indeed, in the absence of DNA damage, the serine/threonine protein phosphatase 2A (PP2A), protein phosphatase 1D (WIP1), and serine/threonine protein phosphatase 1 (PP1) maintain CHK2 in an inactive state, but, at the end of DDR, it is not known if CHK2 is turned off by degradation, dephosphorylation, or phosphorylation of inactivating residues.

In fact, it was reported that in the human cervical cancer cell line, HeLa, and in the ovarian cancer cell line, A2780, the levels of CHK2 protein are reduced respectively after irradiation and cisplatin treatment, and that, in mice, CHK2 phosphorylated on S460 (human S456) is degraded by the proteasome upon ubiquitination by p53-induced RING-H2 protein (PIRH2). In addition, also the phosphatases PP2A and WIP1 may also inactivate CHK2 by dephosphorylation, whereas Polo-like kinase-1 (PLK1), by phosphorylating the CHK2’s FHA domain, reduces the ability of CHK2 to bind phosphorylated proteins and thus to autophosphorylate.

CHK2 Roles in the DNA-Damage Response

Once activated, CHK2 phosphorylates many nuclear proteins, thus regulating different aspects of the DDR. Till now, more than twenty CHK2 targets have been identified (Table 1) and these proteins are mostly involved in DNA repair, cell-cycle regulation, p53 signaling, and apoptosis (Zannini et al. 2014; Magni et al. 2015). CHK2 phosphorylates these substrates on one or more serine or threonine residues and for many of these proteins, phosphorylation occurs at an RXXS or RXXT motif. In addition, some of the proteins phosphorylated by CHK2 are also substrates for ATM activity (BRCA1, BRCA2, KAP-1, and p53), thus suggesting that CHK2 can strengthen or redirect the ATM function.
CHEK2, Table 1

Proteins phosphorylated by CHK2 in response to DNA damage are listed by functional category and the presence of the RXXS/RXXT motifs is indicated


CHK2 substrate

Phosphorylations sites

RXXS or RXXT motif

DNA repair

















Cell cycle















T288, S281

No, No

p53 signaling



T18, S20

No, No


S367, S342

Yes, No











S141, S474, S508

Yes, Yes, Yes










S88, S100, T188

Yes, Yes, No

Other function





















T26, S28, T119

No, No, No

DSBs Repair

In eukaryotic cells, DNA breaks can be rejoined by two different DNA repair pathways (Ciccia and Elledge 2010): nonhomologous end joining (NHEJ) and homology-directed repair (HDR). During NHEJ, the broken DNA ends are directly religated (Lieber 2010). On the contrary, HDR needs a homologous undamaged template but is more accurate than NHEJ and occurs preferentially during S and G2 phases when sister chromatids are present in the cell.

CHK2 is implicated in different repair pathways (Zannini et al. 2014). Indeed, by phosphorylating the two breast cancer susceptibility proteins, BRCA1 and BRCA2, CHK2 favors HDR. In fact, in response to DSBs, the phosphorylation of BRCA1 by CHK2 induces the recruitment to the lesion of Rad51 recombinase, a key player of HDR pathway, and the inhibition of the NHEJ functions of the exonuclease Mre11. In addition, BRCA2 phosphorylation by CHK2 disrupts the Rad51-BRCA2 complex, thus allowing Rad51 association with lesioned sites.

DDR proteins are also known to contribute to chromatin relaxation to facilitate the processing of the breaks, especially in the heterochromatic regions of the genome. In this context, ATM and CHK2 phosphorylate the transcriptional repressor KRAB-associated protein 1 (KAP-1) at two different residues, the former disrupting the complex between KAP-1 and the nucleosome remodeler protein (CHD3) and the latter dissociating the KAP-1/HP1-β interaction. In this way, CHD3 and HP1-β are mobilized from DNA, allowing heterochromatin relaxation and favoring the access of repair factors to lesion sites.

Moreover, CHK2 is also implicated in base excision repair (BER) pathway through the phosphorylation and activation of the transcription factor forkhead box protein M1 (FoxM1), which in turn induces the expression of XRCC1 (Tan et al. 2007).

Cell Cycle Checkpoints Activation

Damaged cells activate cell cycle checkpoints to transiently arrest cell-cycle progression and obtain the necessary time for repairing DNA lesions.

CHK2 is involved in G1/S, intra-S, and G2/M arrest by several mechanisms (Zannini et al. 2014). Indeed, in response to DNA damage, CHK2 phosphorylates the phosphatase Cdc25A inducing its degradation by the proteasome and preventing the dephosphorylation and activation of the cyclin-dependent kinase 2 (Cdk2), which is required for G1 to S transition and S-phase progression. Moreover, CHK2, together with ATM, sustains G1/S arrest by phosphorylating p53 transcription factor and inducing its stabilization and activation. Activated p53 can then promote the transcription of p21, a cyclin-dependent kinases inhibitor, finally leading to a prolonged G1 arrest.

In addition, CHK2, by phosphorylating the phosphatase Cdc25C, is also implicated in G2/M checkpoint activation (Zannini et al. 2014). In fact phosphorylated Cdc25C interacts with 14-3-3 proteins and translocates to the cytoplasm where it cannot dephosphorylate and activate the nuclear cyclinB1/Cdk1 complex, necessary for the G2/M transition. Moreover, CHK2 phosphorylates p53 thus promoting p21 accumulation and sustaining G2 arrest, even if this CHK2 role is still disputed.

Induction of Apoptosis

When cells are too damaged, they activate suicide (apoptotic) pathways to prevent the propagation of a potentially harmful genome. The tumor suppressor protein p53 is a transcription factor that, in response to DNA damage, induces the expression of genes implicated in both checkpoint activation (see above) or, alternatively, in apoptosis regulation (Gomez-Lazaro et al. 2004). CHK2 seems to directly and indirectly regulate p53 activity even if conflicting data about their relationship exist (Zannini et al. 2014). Indeed, a study published in 2000 reported that, upon DNA damage, CHK2 phosphorylates p53 on Ser20 to induce its stabilization, but subsequent studies disputed this finding. Moreover, it is still unclear if p53 phosphorylation by CHK2 induces prosurvival or proapoptotic pathways, and if CHK2 phosphorylates p53 after this protein is stabilized by ATM or if it phosphorylates a latent p53 fraction existing just before DNA damage.

p53 stabilization is also induced by the ATM- and CHK2-dependent phosphorylation of the p53 inhibitor HDMX (Zannini et al. 2014). These phosphorylative events promote HDMX binding to 14-3-3 proteins and its nuclear exclusion. In addition, CHK2 can also activate p53 via the phosphorylation of other proteins, such as Che-1, STRAP, the von Hippel-Lindau tumor suppressor (VHL), and calcineurin binding protein 1 (CABIN1) whose phosphorylation by CHK2 releases their inhibitory activity on p53. CHK2 was also reported to regulate p53 translocation to mitochondria where it directly induces apoptosis in response to IR treatment.

CHK2 also regulates apoptosis by phosphorylating and stabilizing E2F-1, a transcription factor that activates the expression of proapoptotic genes and that is implicated also in CHK2 transcription regulation. Furthermore, in response to DNA damage, CHK2 phosphorylates Hu-antigen R (HuR), a protein involved in binding and stabilizing mRNAs. HuR phosphorylation triggers its dissociation from the NAD+ dependent protein deacetylase sirtuin 1 (SIRT1) mRNA and from virtually all HuR-mRNA complexes, thus regulating apoptosis. Finally, a novel and unexpected role for CHK2 in the induction of anoikis has been discovered.

Premature Cellular Senescence Regulation

After some replication passages, normal diploid cells in culture stop growing and enter a state of senescence. Moreover, cellular senescence has also been described as a barrier to the replication of damaged cells or of cells with activated oncogenes (oncogene-induced senescence, OIS) (Gorgoulis and Halazonetis 2010). Both types of senescence are induced by the shortening of telomeres, chromosome terminal structures similar to DNA breaks and under DDR control. Indeed, normal telomeres are protected by a complex named shelterin (formed by TRF1, TRF2, TPP1, POT1, TIN2, and RAP1 proteins) that prevents chromosome fusions and inhibits DDR kinases. Telomere stress or shortening partially uncovers telomeres leading to ATM and CHK2 activation, permanent cell cycle arrest, and senescence features (Zannini et al. 2014). However, CHK2 substrates involved in senescence are still unknown.

Moreover, in response to DNA damage, ATM and CHK2 phosphorylate TRF2 (Zannini et al. 2014), but while ATM promotes TRF2 relocalization from telomeres to DNA lesions, the role of TRF2 phosphorylation by CHK2 is still unclear.

CHK2 has also been implicated in senescence-associated secretory phenotype (SASP), a process in which senescent cells express and secrete numerous proteins that alter the local tissue environment. SASP is regulated by a pathway involving CHK2, ATM, and the Nijmegen breakage syndrome protein NBS1 (Zannini et al. 2014). Senescence is also associated with persistent nuclear foci containing DDR proteins, named DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), in which active CHK2, PML, and p53 coexist and regulate senescence-associated growth arrest, secretion of IL-6, and senescence sustainment after DNA damage.

CHK2 and the Mitotic Catastrophe

In presence of DNA damage, CHK2 was also described to monitor the effect of the damage on mitotic structures (Matsuoka et al. 1998). Indeed, cells treated with specific CHK2 inhibitors and exposed to DNA-damaging agents enter mitosis and then undergo apoptosis (Castedo et al. 2004), a phenomenon called mitotic catastrophe. Moreover, in DNA-damaged cells, DNA-PKcs phosphorylates CHK2 localized on centrosomes, kinetochores, and midbodies, thus stabilizing centrosomes and spindle formation and preventing mitotic catastrophe.

CHK2 roles in Normal Cellular Physiology

CHK2 in Mitosis and Meiosis

While normal S-phase progression is monitored by the ATR-CHK1 pathway (Maya-Mendoza et al. 2007), CHK2 is implicated in the control of normal M phase. In fact, depletion or inhibition of CHK2 causes abnormal spindle formation, delay of mitosis, and genome instability (Stolz et al. 2010). However, it is still not known if CHK2 acts in this context in the absence of DNA damage or if endogenous lesions induced by highly proliferating cells promote CHK2 activity (Zannini et al. 2014). Moreover, CHK2 was reported to colocalize with its mitotic target BRCA1 on the centrosomes and with PLK1 on the centrosomes and midbody even in the absence of damage, further confirming CHK2’s role in mitosis control.

CHK2 activities independent of exogenous DNA lesions have been reported also in meiosis (Zannini et al. 2014). Indeed, in C. elegans, CHK2 participates to chiasma formation and crossover events, whereas in D. melanogaster a controversial role for CHK2 in the meiotic checkpoint has been reported and the absence of CHK2 has been found to accumulate abnormal nuclei in the syncytial embryo. In addition, in female mice germ cells, CHK2 is activated by ATM during early meiosis and promotes cell cycle progression and spindle assembly during oocyte maturation and early embryo development. Moreover, CHK2 was also reported to remove oocytes with unrepaired meiotic DSBs by activating p53 and p63, possibly reversing female mice infertility due to meiotic recombination defects or irradiation.

CHK2 in Stem Cells

Mutations in DDR proteins are known to lower the success of induced pluripotent stem (iPS) cells stabilization. CHK2 and other DDR proteins are highly expressed in both human embryonic stem (ES) and iPS cells (Momcilovic et al. 2010), consistently with the high repair efficiency detected in these cells and obtained essentially by HDR. Interestingly, in ES cells CHK2 is unable to induce Cdc25A degradation and thus the G1 checkpoint is absent. However, overexpression of DDR proteins could also explain why cancer stem cells are resistant to radiation.

CHK2 and Viral Infection

Viruses are known to alter cell cycle control and DNA replication and, for these reasons, to activate or inhibit the DDR at different stages of infection (Turnell and Grand 2012).

During EBV infection, CHK2 was reported to directly interact with the nuclear antigen 3C (EBNA3C), thus inhibiting G2/M arrest and preventing senescence. Coherently, EBNA3C is essential for immortalization of primary B-lymphocytes in vitro. Moreover, during latent EBV infection, TRF2 is recruited to the EBV origin of replication (OriP) to favor DNA replication, and CHK2 phosphorylates TRF2 during S phase to induce its dissociation from OriP and stabilize episomal DNA (Zannini et al. 2014).

CHK2 is also implicated in the response to the human T-cell leukemia virus type I (HTLV-1) infection (Zannini et al. 2014). In fact, the viral Tax protein binds DNA-PKcs, Ku70, MDC1, BRCA1, and CHK2, forming DNA damage-independent nuclear foci and competing with the normal DDR. Consequently, cells do not sense damage and divide without restrictions. Moreover, repression of DNA repair pathways by HTLV-1 induces genomic instability in the host, supporting cellular transformation to T-cell leukemia.

CHK2 and Mitochondrial DNA Damage

mtDNA is particularly vulnerable because it lacks protective histones, is fully coding and is in close proximity to the inner mitochondrial membrane, where reactive oxygen species and their derivatives are produced.

In budding yeast, the ATM and CHK2 homologs, Tel1 and Rad53, are activated by mitochondrial reactive oxygen species (mtROS) also in the absence of nuclear DNA damage (Schroeder et al. 2013). Also in human cells, there are evidences of the existence of a “mitochondrial checkpoint” regulated by the nuclear DDR and particularly by CHK2 and that failure to repair mtDNA damage induces apoptosis. However, it is still not known how the signal of mtDNA damage reaches CHK2.

CHK2 and the Circadian Clock

A link between the DDR and the circadian clock has been recently reported (Sancar et al. 2010). Specifically, proteins of the human circadian clock, such as period circadian protein 1 (PER1), period circadian protein 3 (PER3), and TIMELESS, interact with CHK2 and seem important for the activation of this kinase (Zannini et al. 2014). In addition, in the bread mold N. crassa, transcription of PRD4, the CHK2 ortholog, has a day/night cycle that peaks in the morning. On the other side, upon DNA damage and in presence of light, PRD4 phosphorylates the frequency clock protein (FRQ), thus signaling DNA lesions to the circadian clock and resetting the circadian rhythm.

CHK2 as a Target for Cancer Therapy

The absence of CHK2 seems to give only mild phenotypes in in vivo and in in vitro cultured normal human cells, exposed or not to genotoxic agents. However, defects associated with the absence of CHK2 are more evident in cells where other DDR factors are impaired. Although, CHK2-/- mice are more susceptible to skin tumors induced by carcinogenic agents, no syndromes or cancer predisposition have been associated with the absence of CHK2 in mice, whereas in contrast, CHK1+/-CHK2-/- and CHK1+/-CHK2+/- mice showed high levels of spontaneous DNA damage and defects in eliminating cells with lesions (Zannini et al. 2014).

In humans, a high incidence of CHK2 germline mutations has been discovered in a number of familial cancers, whereas rare somatic mutations have been found in some tumors (Fig. 4) (Wu et al. 2001). In particular, the CHK2 1100delC and I157T mutations, which lead to a truncated protein with defective enzymatic activity, are considered low-penetrance cancer susceptibility mutations that increase the risk of breast, prostate, ovarian, colorectal, kidney, thyroid, bladder cancers, and leukemias (Wu et al. 2001), making CHK2 a multi-organ tumor susceptibility gene. Moreover, female mice knock in for CHK2*1100delC variant developed spontaneous lung and mammary tumors, suggesting a gender bias in agreement with the hormonal responsiveness of these tissues (Zannini et al. 2014).
CHEK2, Fig. 4

CHK2 mutations in cancer. CHK2 protein primary structure with indicated mutations found in cancer patients. Every spot represents two nonsilent mutations

Therefore, CHK2, similarly to other DDR components, could be considered a target to increase the effect of cancer therapy with DNA-damaging agents. For this reason, small-molecule inhibitors of CHK2 have been tested in clinical trials in combination with other therapies (reviewed in Bucher and Britten 2008), but the results were contrasting, because CHK2 inhibitors are often also active on CHK1, which has a more prominent pro-survival activity. Till now, only CHK1-specific or dual-specificity CHK1/CHK2 inhibitors have entered clinical trials.

Conversely, CHK2 inhibition protects from radiotherapy or chemotherapy, because of its role in the induction of p53-dependent apoptosis, and could sensitize tumors with a p53-deficient background to DNA-damaging therapies, since the absence of both these proteins leads to checkpoints abrogation (Zannini et al. 2014).

Also, agents that can alter telomeric structures may be able to kill tumor cells characterized by long telomeres, since these drugs induce the activation of the ATM-CHK2 response finally leading to autophagy (Zannini et al. 2014).

Thus, it is clear that, for cancer therapy, the choice between CHK2 inhibition and activation depends on the kind, magnitude, and duration of exposure to the damaging agent, on the genetic background of the cancer cells, and on the specificity and efficacy of the CHK2 inhibitor. However, additional studies are necessary before using these molecules to treat cancer.


CHK2 is a serine/threonine kinase with a main role in the DDR, especially in response to DSBs. In human cells, CHK2 is activated by ATM upon genotoxic stress and phosphorylates more than 20 substrates to induce the appropriate cellular response that could be DNA repair, cell-cycle checkpoint activation, induction of apoptosis, or senescence depending on the type and extent of damage. Moreover, in unstressed conditions, CHK2 participates in several other molecular processes implicated in the maintenance of DNA structure and cell cycle progression regulation, like mitosis and meiosis, virus infection, or circadian clock.

However, it is clear that CHK2’s role in the DDR and in the physiological cellular functions is still not completely understood. Although much has been disclosed about CHK2 function since its discovery, further studies are necessary to understand the mechanisms involved in CHK2 activation and mostly inactivation. We expect that in the next few years, new CHK2 substrates will be probably identified by proteomic approaches and wide-screening analyses. These findings will help to define those mechanisms and proteins that fine-tune the different biological outcomes of the DDR and the possibility of treating specific tumors by CHK2 activation or inactivation, alone or in combination with other therapies. However, we need to define the variables and the conditions supporting the use of CHK2 inhibitors to treat cancer in a personalized manner.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiosciencesUniversità degli Studi di MilanoMilanItaly
  2. 2.Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly