loki/chk2: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References
Gene name - loki

Synonyms - chk2, Dmnk

Cytological map positions - 38B

Function - signaling

Keywords - cell cycle, meiotic checkpoint, response to DNA damage, cellularization, p53 pathway, apoptosis

Symbol Symbol - lok

FlyBase ID: FBgn0019686

Genetic map position -

Classification - protein serine/threonine kinase

Cellular location - nuclear



NCBI links: Precomputed BLAST | Entrez Gene | UniGene |
Recent literature
Molla-Herman, A., Vallés, A.M., Ganem-Elbaz, C., Antoniewski, C. and Huynh, J.R. (2015). tRNA processing defects induce replication stress and Chk2-dependent disruption of piRNA transcription. EMBO J [Epub ahead of print]. PubMed ID: 26471728
Summary:
RNase P is a conserved endonuclease that processes the 5' trailer of tRNA precursors. This study isolated mutations in Rpp30, a subunit of RNase P, and found that these induce complete sterility in Drosophila females. It was shown that sterility is not due to a shortage of mature tRNAs, but that atrophied ovaries result from the activation of several DNA damage checkpoint proteins, including p53, Claspin, and Chk2. Indeed, tRNA processing defects lead to increased replication stress and de-repression of transposable elements in mutant ovaries. Transcription of major piRNA sources collapse in mutant germ cells and that this correlates with a decrease in heterochromatic H3K9me3 marks on the corresponding piRNA-producing loci. These data thus link tRNA processing, DNA replication, and genome defense by small RNAs. This unexpected connection reveals constraints that could shape genome organization during evolution.

Shaposhnikov, M., Proshkina, E., Shilova, L., Zhavoronkov, A. and Moskalev, A. (2015). Lifespan and stress resistance in Drosophila with overexpressed DNA repair genes. Sci Rep 5: 15299. PubMed ID: 26477511
Summary:
DNA repair declines with age and correlates with longevity in many animal species. This study investigated the effects of GAL4-induced overexpression of genes implicated in DNA repair on lifespan and resistance to stress factors in Drosophila melanogaster. Stress factors included hyperthermia, oxidative stress, and starvation. Overexpression was either constitutive or conditional and either ubiquitous or tissue-specific (nervous system). Overexpressed genes included those involved in recognition of DNA damage (homologs of HUS1, CHK2), nucleotide and base excision repair (homologs of XPF, XPC and AP-endonuclease-1), and repair of double-stranded DNA breaks (homologs of BRCA2, XRCC3, KU80 and WRNexo). The overexpression of different DNA repair genes led to both positive and negative effects on lifespan and stress resistance. Effects were dependent on GAL4 driver, stage of induction, sex, and role of the gene in the DNA repair process. While the constitutive/neuron-specific and conditional/ubiquitous overexpression of DNA repair genes negatively impacted lifespan and stress resistance, the constitutive/ubiquitous and conditional/neuron-specific overexpression of Hus1, Mnk/Chk2, mei-9, mus210, and WRNexo had beneficial effects. This study demonstrates for the first time the effects of overexpression of these DNA repair genes on both lifespan and stress resistance in D. melanogaster.
Nagy, P., Sandor, G. O. and Juhasz, G. (2018). Autophagy maintains stem cells and intestinal homeostasis in Drosophila. Sci Rep 8(1): 4644. PubMed ID: 29545557
Summary:
Intestinal homeostasis is maintained by tightly controlled proliferation and differentiation of tissue-resident multipotent stem cells during aging and regeneration, which ensures organismal adaptation. This study shows that autophagy is required in Drosophila intestinal stem cells to sustain proliferation, and preserves the stem cell pool. Autophagy-deficient stem cells show elevated DNA damage and cell cycle arrest during aging, and are frequently eliminated via JNK-mediated apoptosis. Interestingly, loss of Chk2, a DNA damage-activated kinase that arrests the cell cycle and promotes DNA repair and apoptosis, leads to uncontrolled proliferation of intestinal stem cells regardless of their autophagy status. Chk2 accumulates in the nuclei of autophagy-deficient stem cells, raising the possibility that its activation may contribute to the effects of autophagy inhibition in intestinal stem cells. This study reveals the crucial role of autophagy in preserving proper stem cell function for the continuous renewal of the intestinal epithelium in Drosophila.
BIOLOGICAL OVERVIEW

In response to DNA damage, eukaryotic cells use a system of checkpoint controls to delay cell-cycle progression. Checkpoint delays provide time for repair of damaged DNA before its replication in S phase and before segregation of chromatids in M phase. The Chk2 tumor-suppressor protein has been implicated in certain checkpoint responses in mammalian cells. It directly phosphorylates and inactivates the mitosis-inducing phosphatase Cdc25 (see Drosophila String) in vitro and is required to maintain the G2 arrest that is observed in response to gamma-irradiation. Chk2 also directly phosphorylates p53 (see Drosophila p53) in vitro at a site that is implicated in its stabilization, and is required for stabilization of p53 and induction of p53-dependent transcripts in vivo upon gamma-ionizing radiation. Thus, Chk2 functions in both the G1 and G2 checkpoint responses. Like Chk2, the checkpoint protein kinase ATM (ataxia-telangiectasia-mutated) is required for correct operation of both the G1 and G2 damage checkpoints. ATM is necessary for phosphorylation and activation of Chk2 in vivo and can phosphorylate Chk2 in vitro (Xu, 2001; Abdu, 2002; Masrouha, 2003; and references therein).

The Drosophila serine/threonine kinase Loki (Entree Nucleotide record), here referred to alternatively as Dmnk (Oishi, 1998) or Drosophila Chk2, is the homolog of the yeast Mek1p, Rad53p, Dun1p, and Cds1 proteins as well as the human Chk2. Functional analyses led to the conclusion that, in flies, Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis (Xu, 2001). chk2 acts during early embryogenesis to monitor double-strand breaks (DSBs) caused by irradiation during S and G2 phases (Masrouha, 2003). Abdu (2002) presents convincing evidence that chk2 is part of a meiotic checkpoint functioning during oogenesis. The target of this signal is thought to be Vasa, which in turn regulates the translation of Gurken mRNA. Drosophila chk2 does not act at the same cell cycle phases as its yeast homologs, but seems rather to be involved in a pathway similar to the mammalian one, which involves signaling through the ATM/Chk2 pathway in response to genotoxic insults. Since mutations in human chk2 have been linked to several cancers, these similarities underscore the usefulness of the Drosophila model system (Masrouha, 2003).

In the mammalian system, Chk2 is a key player in maintaining the genome integrity. In the G1 checkpoint, ionizing radiation (IR) exposure can activate the ATM-Chk2 pathway. Activated Chk2 phosphorylates Ser123 in Cdc25A, targeting it for ubiquitin-dependent degradation (Falck, 2001). Since Cdc25A is downregulated, the activity of CyclinA-Cdk2 is inhibited and replication is slowed. In addition, downregulation of Cdc25A is thought to inhibit the activity of CyclinE-Cdk2, leading to the p53-independent initiation of the G1 checkpoint (Bartek, 2001a). In the G2/M checkpoint, Chk1 (Drosophila homolog: Grapes), Chk2, and p53 are three key transducers: the ATM and Rad 3-related (ATR)-Chk1 pathway is thought to be activated when cells are exposed to IR during G1 or S phase; the ATM-Chk2 pathway is thought to arrest cells in response to genotoxic insults during G2 phase (Abraham, 2001); recent findings indicate that p53 may play additional roles to help cells arrest at the G2/M transition (Taylor, 2001). Checkpoint signals relayed from Chk1, Chk2, and p53 arrest the cell cycle at the G2/M transition via downregulation of the kinase activity of CyclinB-Cdk1. Depending on the transducer, this downregulation step can involve one of the following intermediates: Cdc25C, p21, Gadd45, or 14-3-3 (Masrouha, 2003 and references therein).

ATM activates human Chk2 (hChk2) by phosphorylating an amino terminal Thr residue (Thr 68) (Ahn, 2000; Melchionna, 2000), and hChk2, in turn, phosphorylates p53 on two sites, Serine 15 and Serine 20. The location of Ser 15 at the p53 amino terminus suggested that modification of this residue might trigger the dissociation of p53 from MDM2, a protein that targets p53 for ubiquitination, nuclear export, and proteosomal degradation. Therefore, if the model were correct, ATM/ATR-dependent phosphorylation of Ser 15 would free p53 from its destabilizing binding partner, thereby favoring p53 accumulation. It turns out, however, that Ser 15 phosphorylation is not sufficient to disrupt the p53-MDM2 interaction; rather, this modification stimulates the transactivating function of p53 by enhancing the binding of this protein to the transcriptional coactivator, p300. However, these results do not rule out the possibility that phosphorylation of p53 at Ser 15 sets this protein up for a secondary modification that does modify the binding of MDM2 to p53, thereby inhibiting p53 degradation. Indeed, Ser 15 phosphorylation greatly enhances the subsequent phosphorylation of p53 at Ser 18 by casein kinase I, at least under test-tube assay conditions with purified proteins. The presence of phosphates at Ser 15 and Ser 18 reduces the avidity of full-length p53 for MDM2 by approximately threefold. Further studies are required to determine whether, and under what conditions, the tandem modification of p53 by ATM/ATR and casein kinase I contributes to p53 accumulation in intact cells. Chk2 phosphorhylates yet another amino-terminal Ser residue (Ser 20) in p53 (Chehab, 2000; Hirao, 2000; Shieh, 2000). Unlike the Ser 15 modification of Chk2 by ATM, phosphorylation at Ser 20 interferes directly with the binding of p53 to MDM2, thereby favoring p53 accumulation in response to IR-induced DNA damage. The physiological relevance of hChk2 in the regulation of p53 is supported by the finding that loss-of-function mutations in hChk2 can give rise to a variant form of Li-Fraumeni syndrome (Bell, 1999), a heritable, cancer-prone disorder typically associated with germ-line mutations in p53 (Abraham, 2001 and references therein).

In Drosophila, Chk2 appears to act to regulate the apoptotic activity of p53 during genotoxic stress. The tumor suppressor function of p53 has been attributed to its ability to regulate apoptosis and the cell cycle. In mammals, DNA damage, aberrant growth signals, chemotherapeutic agents, and UV irradiation activate p53, a process that is regulated by several posttranslational modifications. Overexpression of Drosophila p53 (p53) in the eye induces apoptosis, resulting in a small eye phenotype. This phenotype is markedly enhanced by coexpression with Drosophila Chk2 and was almost fully rescued by coexpression with a dominant-negative (DN), kinase-dead form of Chk2. DN Chk2 also inhibits p53-mediated apoptosis in response to DNA damage, whereas overexpression of Grapes (Grp), the Drosophila Chk1-homolog, and its DN mutant has no effect on p53-induced phenotypes. Chk2 also activates the p53 transactivation activity in cultured cells. Mutagenesis of p53 amino terminal Ser residues reveals that Ser-4 is critical for its responsiveness toward Chk2. Chk2 activates the apoptotic activity of p53 and Ser-4 is required for this effect. Contrary to results in mammals, Grapes, the Drosophila Chk1-homolog, is not involved in regulating p53. Chk2 may be the ancestral regulator of p53 function (Peters, 2002).

Since maternal Chk2 protein expression persists into embryonic development, the gene may function during early embryogenesis; it was of interest to determine whether chk2 functions in DNA damage checkpoint activation in 3- to 4-hr-old embryos, which are in cycle 14. During cycle 14, cells are known to enter mitosis as stereotypical clusters called 'mitotic domains'. The timing of entry into mitosis of each one of these domains as well as the morphogenetic movements that comprise gastrulation are known to be invariant between different embryos. It was furthermore observed that DNA damage induced by irradiation or MMS treatment can delay entry into mitosis of cycle 14 (Su, 2000); this delay is primarily due to inhibitory phosphorylation of Cdk1, and nuclear exclusion of the Cdk1-Cyclin complex might also play a secondary role (Masrouha, 2003).

Embryos in interphase 14 (130- to 200-min-old embryos) were exposed to 600 rad of gamma-irradiation, which corresponds to the half-lethal dose. Irradiated embryos were allowed to recover for 45 min, after which they were fixed and stained for the mitotic-specific phospho-Histone3 (PH3) epitope. At the same time these embryos were stained for Vasa, a pole-cell-specific marker that shows the progression of the morphogenetic movements of gastrulation. In nonirradiated wild-type embryos, domain 1 initiates mitosis in stage 6. In wild-type embryos, irradiation causes a delay of entry into mitosis. For instance, domain 1 does not start mitosis until much later after irradiation (stage 8). In nonirradiated chk2null mutant embryos, mitotic patterns in each specific gastrulation stage are the same as in the nonirradiated wild-type embryos. However, in irradiated chk2null mutant embryos, each mitotic domain enters mitosis with the same timing as the nonirradiated control, indicating that the DNA damage checkpoint is defective. Similar defects in arresting the cell cycle were observed in irradiated chk2null embryos that were allowed to recover for only 15 min after the gamma-ray exposure. Since S and G2 phases of cycle 14 last 50 and 20 min, respectively, this finding shows that chk2 is a damage checkpoint gene involved in mediating responses to DSBs induced during the S or G2 phases of the cell cycle. Thus, chk2 is required for the DNA damage checkpoint in somatic cells. It thus appears that low Chk2 levels are sufficient for this checkpoint to be active (Masrouha, 2003).

In S. cerevisiae, the Chk2 family member Rad53p is required for the DNA damage and replication checkpoint and arrests the cell cycle at the G1/S transition, in S phase, or at the metaphase-anaphase transition in response to stresses. Nevertheless, Rad53p is not required for the meiotic pachytene checkpoint. Instead, a meiotic-specific version, Mek1p, is required for detecting DNA DSBs that arise as recombination occurs. In S. pombe, the Chk2 family member, Cds1, is mainly required for the S-phase DNA damage/replication checkpoint. Activated Cds1 arrests cells in S phase in response to unreplicated DNA or damaged DNA sensed during S phase. Whether Cds1 is required for the meiotic checkpoint is not yet known. Mammalian Chk2 is indispensable for G1/S, S, and G2/M checkpoint controls, but its role in the meiotic checkpoint is not clear. These functional and temporal divergences between the different CHK2 orthologs indicate that this protein kinase family displays an amazing degree of evolutionary plasticity (Meier, 2001). This plasticity is further supported when one compares C. elegans and Drosophila chk2. While the former has been shown to be required for meiotic chromosome pairing but is dispensable for typical DNA damage/replication checkpoint responses induced by gamma-irradiation or by HU, the results presented in the Masrouha study (2003) show that chk2 has no essential function in Drosophila meiosis. It is involved, however, in monitoring DSBs induced by gamma-rays, which places it closer to its vertebrate homologs and makes it an excellent invertebrate model for studying human chk2 function (Masrouha, 2003).

Calling some of these findings into doubt is a study by Abdu (2002), dealt with in more detail in the Effects of Mutation section. Abdu (2002) presents convincing evidence that chk2 transduces the DSB signal. The target of this signal is thought to be Vasa, which in turn regulates the translation of Gurken mRNA. Resolving this contradiction will require a number of follow-up experiments (Masrouha, 2003).

DNA damage-induced CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

This study used germline stem cells (GSCs) in the Drosophila ovary to show that DNA damage retards stem cell self-renewal and lineage differentiation in a CHK2 kinase-dependent manner. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and an accumulation of ill-differentiated GSC progeny. Elimination of CHK2 or its kinase activity can almost fully rescue the GSC loss and the progeny differentiation defect caused by DNA damage induced by I-CreI or X-ray. Surprisingly, checkpoint kinases ATM and ATR have distinct functions from CHK2 in GSCs in response to DNA damage. The reduction in BMP signaling and E-cadherin only makes limited contribution to DNA damage-induced GSC loss. Finally, DNA damage also decreases the expression of the master differentiation factor Bam in a CHK2-dependent manner, which helps explain the GSC progeny differentiation defect. Therefore, this study demonstrates, for the first time in vivo, that CHK2 kinase activation is required for the DNA damage-mediated disruption of adult stem cell self-renewal and lineage differentiation, and might also offer novel insight into how DNA damage causes tissue aging and cancer formation. It also demonstrates that inducible I-CreI is a convenient genetic system for studying DNA damage responses in stem cells (Ma, 2016).

Stem cells in adult tissues are responsible for generating new cells to combat against aging, and could also be cellular targets for tumor formation. Although aged stem cells have been shown to accumulate DNA damage, it remains largely unclear how DNA damage affects stem cell self-renewal and differentiation. A previous study has reported that upon weak irradiation apoptotic differentiated GSC progeny can prevent GSC loss by activating Tie-2 receptor tyrosine kinase signaling (Xing, 2015). This study shows that temporally introduced DNA double-stranded breaks cause premature GSC loss and slow down GSC progeny differentiation. Mechanistically, DNA damage causes GSC loss at least via two independent mechanisms, down-regulation of BMP signaling and E-cadherin-mediated GSC-niche adhesion as well as CHK2 activation- dependent GSC loss. In addition, CHK2 activation also decreases Bam protein expression by affecting its gene transcription and translation, slowing down CB differentiation into mitotic cysts and thus causing the accumulation of CB-like cells. Surprisingly, unlike in many somatic cell types, ATM, ATR, CHK1 and p53 do not work with CHK2 in DNA damage checkpoint control in Drosophila ovarian GSCs. Therefore, this study demonstrates that DNA damage-induced CHK2 activation causes premature GSC loss and also retards GSC progeny differentiation. The findings could also offer insight into how DNA damage affects stem cell-based tissue regeneration. In addition, this study also shows that the inducible I-CreI system is a convenient method for studying stem cell responses to transient DNA damage because it does not require any expensive irradiation equipment as the X-ray radiation does (Ma, 2016).

DNA damage normally leads to cell apoptosis to eliminate potential cancer- forming cells. This study, shows that transient DNA damage causes GSC loss not through apoptosis based on twopieces of experimental evidence: first, DNA-damaged GSCs are not positive for the cleaved Caspase-3, a widely used apoptosis marker; Second, forced expression of a known apoptosis inhibitor p35 does not show any rescue effect on DNA damage-induced GSC loss. Thus, DNA damage-induced GSC loss is likely due to self-renewal defects though the possibility could not be ruled out that other forms of cell death are responsible. p53 is known to be required for DNA damage-induced apoptosis from flies to humans. This study, however, demonstrates that p53 prevents the DNA damage-induced GSC loss. Vacating DNA-damaged GSCs from the niche via differentiation might allow their timely replacement and restoration of normal stem cell function. Therefore, the findings argue strongly that DNA damage primarily compromises self-renewal, thus causing GSC loss. Both niche-activated BMP signaling and E-cadherin-mediated cell adhesion are essential for GSC self-renewal. Consistent with the idea that DNA damage compromises GSC self-renewal, it significantly decreases BMP signaling activity and apical accumulation of E-cadherin in GSCs. Since constitutively active BMP signaling alone or in combination with E-cadherin overexpression can only moderately rescue GSC loss caused by DNA damage, it is concluded that decreased BMP signaling and apical E-cadherin accumulation might partly contribute to the DNA damage-induced GSC loss. Therefore, the findings suggest that DNA damage-mediated down-regulation of BMP signaling and E-cadherin-mediated adhesion only moderately contributes to the GSC loss (Ma, 2016).

DNA damage leads to checkpoint activation and cell cycle slowdown, thus giving more time for repairing DNA damage. In various cell types, ATM-CHK2 and ATR-CHK1 kinase pathways are responsible for DNA damage-induced checkpoint activation. During Drosophila meiosis, ATR, but not ATM, is required for checkpoint activity, indicating that ATM and ATR could have different functions in germ cells. Both ATR and CHK2 have been shown to be required for DNA damage-evoked checkpoint control in Drosophilagerm cells and embryonic cells, while CHK1 can control the entry into the anaphase of cell cycle in response to DNA damage, the G2-M checkpoint activation as well as the Drosophila midblastula transition (Ma, 2016).

This study has shown that these four checkpoint kinases function differently in GSCs. First, CHK2 is required for DNA damage-induced GSC loss, but is dispensable for normal GSC maintenance. Particularly, inactivation of its kinase activity can almost fully rescue DNA damage-induced GSC loss. Interestingly, inactivation of CHK2 function can also rescue the female germ cell defect caused by DNA damage in the mouse ovary, indicating that CHK2 function in DNA damage checkpoint activation is conserved at least in female germ cells. However, it remains unclear if CHK2 behaves similarly in mammalian stem cells in response to DNA damage. Second, ATM promotes GSC maintenance in the absence and presence of DNA damage. This is consistent with the finding that ATM is required for the maintenance of mouse male germline stem cells and hematopoietic stem cells. It will be interesting to investigate if ATM also prevents the oxidative stress in Drosophila GSCs as in mouse hematopoietic stem cells. Third, ATR is dispensable for normal GSC maintenance, but it protects GSCs in the presence of DNA damage. Although CHK2 and ATR behave similarly in DNA damage checkpoint control during meiosis and late germ cell development, they behave in an opposite way in GSCs in response to DNA damage. Finally, CHK1 is dispensable for GSC self-renewal in the absence and presence of DNA damage. Consistent with the current findings, the females homozygous for grp, encoding CHK1 in Drosophila, can still normally lay eggs, but those eggs could not develop normally. It will be of great interest in the future to figure out how CHK2 inactivation prevents DNA damage-induced GSC loss and how ATM and ATR inactivation promotes DNA damage-induced GSC loss at the molecular level. A further understanding of the functions of CHK2, ATM and ATR in stem cell response to DNA damage will help preserve aged stem cells and prevent their transformation into CSCs. DNA damage-evoked CHK2 activation retards GSC progeny differentiation by decreasing Bam expression at least at two levels This study has also revealed a novel mechanism of how DNA damage affects stem cell differentiation. Bam is a master differentiation regulator controlling GSC- CB and CB-cyst switches in the Drosophila ovary: CB-like single germ cells accumulate in bam mutant ovaries, whereas forced Bam expression sufficiently drives GSC differentiation. This study shows that DNA damage causes the accumulation of CB-like cells in a CHK2- dependent manner because CHK2 inactivation can fully rescue the germ cell differentiation defect caused by DNA damage. In addition, a heterozygous bam mutation can drastically enhance, and forced bam expression can completely repress, the DNA damage-induced germ cell differentiation defect, indicating that DNA damage disrupts Bam-dependent differentiation pathways. Consistently, Bam protein expression is significantly decreased in DNA damaged mitotic cysts in comparison with control ones. Interestingly, CHK2 inactivation can also fully restore Bam protein expression levels in the DNA-damaged mitotic cysts. Taken together, CHK2 activation is largely responsible forBam down-regulation in DNA damaged mitotic cysts, which can mechanistically explain the DNA damage-induced germ cell differentiation defect. It was further shown that DNA damage decreases Bam protein expression at least at two different levels. First, the bam transcription reporter bam-gfp was used to show that DNA damage decreases bamtranscription in CBs and mitotic cysts. Second, the posttranscriptional reporter Pnos-GFP-bam 3'UTR was generated to show that DNA damage decreases Bam protein expression via its 3'UTR in CBs and mitotic cysts at the level of translation. Although the detailed molecular mechanisms underlying regulation of Bam protein expression by DNA damage await future investigation, these findings demonstrate that DNA damage causes the GSC progeny differentiation defect by decreasing Bam protein expression at transcriptional and translational levels (Ma, 2016).

Taken together, these findings from Drosophila ovarian GSCs could offer important insight into how DNA damage affects stem cell-based tissue regeneration, and have also established Drosophila ovarian GSCs as a new paradigm for studying how DNA damage affects stem cell behavior at the molecular level. Because many stem cell regulatory strategies are conserved from Drosophilato mammals, what has been learned from this study should help understand how mammalian adult stem cells respond to DNA damage (Ma, 2016).


GENE STRUCTURE

cDNA clone length - 2059 (short form)

Bases in 5' UTR - 270

Exons - 6

Bases in 3' UTR - 409


PROTEIN STRUCTURE

Amino Acids - 459 and 476 (long form)

Structural Domains

A phylogenetic analysis was performed with Loki and its most similar sequences. The Loki polypeptide sequence identified 48 sequences with considerable identity (>25%) in the NCBI databases using the BLAST algorithm. The most conserved sequence, the kinase domain, was then used to perform a multiple alignment that served to generate the phylogenetic tree. The neighbor-joining phylogeny produced a high percentage (94%) branched clade containing Loki, Chk2, Mek1p, Rad53p, Cds1, and Dun1p. In addition, Loki contains a FHA domain (52-112 aa) followed by a kinase domain (157-424 aa), which is the distinguishing feature of Rad53p, Mek1p, Dun1p, Cds1, and Chk2. It is thus likely to have a similar checkpoint function in flies as its homologs in their respective organisms (Masrouha, 2003).


loki/chk2: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 8 June 2003

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