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Sibling rivalry in checkpoint control of cell cycle and DNA damage response a
a
Navjotsingh Pabla & Zheng Dong a
Department of Cellular Biology and Anatomy; Medical College of Georgia; Georgia Health Sciences University and Charlie Norwood Veterans Affairs Medical Center; Augusta, GA USA Published online: 15 May 2012.
To cite this article: Navjotsingh Pabla & Zheng Dong (2012) Sibling rivalry in checkpoint control of cell cycle and DNA damage response, Cell Cycle, 11:10, 1866-1867, DOI: 10.4161/cc.20416 To link to this article: http://dx.doi.org/10.4161/cc.20416
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Editorials: Cell Cycle Features
Cell Cycle 11:10, 1866-1867; May 15, 2012; © 2012 Landes Bioscience
Sibling rivalry in checkpoint control of cell cycle and DNA damage response Navjotsingh Pabla† and Zheng Dong Department of Cellular Biology and Anatomy; Medical College of Georgia; Georgia Health Sciences University and Charlie Norwood Veterans Affairs Medical Center; Augusta, GA USA
Downloaded by [176.205.197.139] at 15:49 26 August 2015
†
Current affiliation: Division of Biology; California Institute of Technology; Pasadena, CA USA
Maintenance of genomic stability is vital for the survival of all organisms. As a result highly conserved regulatory mechanisms have evolved in eukaryotes that block cell division until the accurate duplication of genomic DNA is completed. These “checkpoint” pathways constitute the key regulatory nodes that ensure genomic stability during normal cell cycle.1,2 Presence of un-replicated and/or damaged DNA results in activation of the DNA damage response (DDR) pathways, which, in turn, negatively regulate the proteins required for cell cycle progression, resulting in checkpoint activation.1 The DDR pathway is thus the predominant regulatory process responsible for the maintenance of genomic stability. One of the most important components of DDR is the ATR-Chk1 pathway. ATR (ataxia telangiectasia and Rad3-related protein) is a protein kinase belonging to the PIKKs family, which is an essential regulator of cell cycle checkpoints.3,4 Accumulation of single-stranded DNA during normal DNA replication and DDR is the primary signal for ATR activation.3,4 The complex regulatory steps required for ATR activation and the downstream substrates that mediate checkpoint activation has been a subject of extensive investigations.3,5 These studies have shown that the presence of single-stranded DNA results in activation of ATR, which is dependent on multiple regulatory proteins; ATR further phosphorylates numerous proteins, including checkpoint kinase-1 (Chk1); Chk1, in turn, induces checkpoint activation and cell cycle arrest by targeting cell cycle-regulatory proteins.6
Chk1 is an essential and highly conserved serine/threonine kinase present in all eukaryotes.7 Since its discovery in yeast as a key regulator of cell cycle progression, important mechanistic insights have been gained into its regulation and function. These studies have provided evidence that during DDR, Chk1 is phosphorylated at conserved sites in an ATRdependent manner. Chk1 further targets multiple cell cycle regulatory proteins like cdc25 to block cell cycle progression and promote DNA repair. These studies have established that Chk1 is a critical cell cycle regulator with significant biological roles. While Chk1 phosphorylation is critical for checkpoint activation during both normal cell cycle progression and DDR, it is unclear how phosphorylation regulates Chk1 activity. Our recent study has deciphered a novel component in the regulation of Chk1 activity.8 We have identified a ubiquitously expressed alternative splice variant of Chk1, which is a critical determinant of Chk1 activity and function. Chk1-S is a N-terminally truncated splice variant of Chk1 that acts as an endogenous inhibitor of Chk1 activity. In unperturbed cell cycle, Chk1-S is induced during late S-G2 phase and inhibits Chk1 activity to promote cell cycle progression. Intriguingly, Chk1-S can directly interact with Chk1, and this interaction is disrupted when Chk1 is phosphorylated during DDR. These observations have provided evidence that Chk1-S may be a key regulator of Chk1 activity during both normal cell cycle progression and DDR. Until very recently, it had been believed that Chk1 phosphorylation leads
to its activation by relieving inhibitory effect of the C-terminal domain on the N-terminal kinase domain.7 However, structural studies showed that Chk1 is present in an open conformation. Also, the Chk1-S345A mutant is biologically inactive but has kinase activity comparable to wild-type Chk1.9 It has been suggested that phosphorylation of Chk1 de-represses its activity. Our study shows that Chk1-S might be one of the factors that repress Chk1 activity. Based on our work, we have proposed a model that is summarized in Figure 1. During unperturbed cell cycle, Chk1 expression and activity is high during the entire S phase, ensuring that cells do not enter mitosis before the completion of DNA replication. During late S phase, the expression of Chk1-S increases; Chk1-S binds to Chk1 and inhibits its activity. Chk1 inhibition during late S phase results in timely entry into G2 /M phase. When Chk1-S is overexpressed, Chk1 activity is neutralized before the completion of DNA replication, and cells prematurely enter mitosis and undergo mitotic catastrophe. When Chk1-S expression is reduced, Chk1 activity remains high, and cell cycle progression is blocked, leading to lower cellular proliferation. Importantly, during DDR, Chk1-S is not able to bind Chk1 due to its phosphorylation, resulting in high Chk1 activity and checkpoint activation. Thus Chk1-S provides a regulatory switch in the temporal regulation of Chk1 activity. Alternative splicing is a key mechanism that provides proteomic diversity.10 Multiple cell cycle and DDR proteins are alternatively spliced; although the
© 2012 Landes Bioscience. Do not distribute.
Correspondence to: Navjotsingh Pabla and Zheng Dong; Email:
[email protected] and
[email protected] Submitted: 04/04/12; Accepted: 04/11/12 http://dx.doi.org/10.4161/cc.20416 Comment on: Pabla N, et al. Proc Natl Acad Sci USA 2012; 109:197–202; PMID:22184239; http://dx.doi.org/10.1073/pnas.1104767109. 1866
Cell Cycle
Volume 11 Issue 10
Editorials: Cell Cycle Features
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Editorials: Cell Cycle Features
© 2012 Landes Bioscience. Do not distribute.
Figure 1. Chk1/Chk1-S regulation of cell cycle and DNA damage response. In unperturbed cell cycle, Chk1-S is induced in late S phase to bind and inactivate Chk1, resulting in S-G2/M transition and cell cycle progression. During DNA damage response, ATR-mediated phosphorylation of Chk1 reduces its interaction with Chk1-S, leading to high Chk1 activity and cell cycle arrest.
functional and biological implications are not clear in most cases. One of the main challenges would be to identify the key regulatory proteins required for the alternative splicing of Chk1 gene. Identification of regulatory proteins required for alternative splicing of Chk1 could provide new insights into the role of alternative splicing in DDR and cell cycle regulation. Another important question that remains to be addressed is to determine if Chk1-S is conserved in lower eukaryotes, including yeast. In addition, we detected high Chk1-S expression in cancer tissues.8 Why? Is the higher expression of Chk1-S in cancer
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tissues due to their proliferative nature, or does Chk1-S play a role in tumorigenesis? These are important questions that remain to be answered. Further investigation of the function and regulation of Chk1-S could have important biological and biomedical implications. References 1. Ciccia A, et al. Mol Cell 2010; 40:179-204; PMID:20965415; http://dx.doi.org/10.1016/j.molcel.2010.09.019. 2. Jackson SP, et al. Nature 2009; 461:1071-8; PMID:19847258; http://dx.doi.org/10.1038/ nature08467. 3. Cimprich KA, et al. Nat Rev Mol Cell Biol 2008; 9:61627; PMID:18594563; http://dx.doi.org/10.1038/ nrm2450.
Cell Cycle
4. Nam EA, et al. Biochem J 2011; 436:527-36; PMID:21615334; http://dx.doi.org/10.1042/ BJ20102162. 5. Matsuoka S, et al. Science 2007; 316:1160-6; PMID:17525332; http://dx.doi.org/10.1126/science.1140321. 6. Bartek J, et al. Cancer Cell 2003; 3:421-9; PMID:12781359; http://dx.doi.org/10.1016/S15356108(03)00110-7. 7. Tapia-Alveal C, et al. Cell Div 2009; 4:8; PMID:19400965; http://dx.doi.org/10.1186/17471028-4-8. 8. Pabla N, et al. Proc Natl Acad Sci USA 2012; 109:197202; PMID:22184239; http://dx.doi.org/10.1073/ pnas.1104767109. 9. Walker M, et al. Oncogene 2009; 28:2314-23; PMID:19421147; http://dx.doi.org/10.1038/ onc.2009.102. 10. Kalsotra A, et al. Nat Rev Genet 2011; 12:715-29; PMID:21921927; http://dx.doi.org/10.1038/nrg3052.
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