Cell Cycle Effects in Radiation Oncology

  • Randi G. SyljuåsenEmail author
Living reference work entry


Cells in the human body can be either dividing or nondividing. In order to undergo cell division, the cycling cells sequentially enter four different cell cycle phases: G1, S, G2, and M. It has long been known that cells in different cell cycle phases display different radiosensitivity. Cells in late S phase are usually most radioresistant and cells in M phase most radiosensitive. One of the classical four “R”s describing the rationale behind fractionated radiotherapy is based on such cell cycle differences, as fractionation allows tumor cells in a radioresistant cell cycle phase to “Redistribute” into more radiosensitive phases before the next fractions. Furthermore, some chemotherapeutic or targeted drugs applied in combination with radiation therapy can cause the tumor cells to accumulate in radioresistant or radiosensitive cell cycle phases, thereby altering the tumor radiosensitivity. It is also well known that radiation halts cell cycle progression through inducing arrest at the cell cycle checkpoints. Three major radiation-induced cell cycle checkpoints exist, in G1, S, and G2 phase. Because most irradiated tumor cells do not die before attempting to divide, the checkpoints are important to allow time for repair of the radiation damage. The G1 checkpoint is dependent on the tumor suppressor p53 and is often deficient or lacking in tumor cells. Tumor cells may therefore rely more on the S and G2 checkpoints for repair of radiation damage compared to normal cells. One strategy for obtaining tumor selective radiosensitization is thus to combine radiation with drugs that abrogate the G2 checkpoint.


Cell cycle checkpoints Radiosensitivity Cell cycle phase Checkpoint kinases ATR, Chk1 and Wee1 

The Cell Cycle Phases and Radiosensitivity

In order to divide and produce two identical daughter cells, human cells pass through several cell cycle phases (Fig. 1). Resting, nondividing, cells are in G0-phase and may be able to enter the cell cycle depending on growth factors and other stimuli. In G1-phase cells are growing and preparing for DNA replication. The DNA replication thereafter takes place during S-phase, where the cellular DNA content is duplicated. After S-phase, the cells enter G2-phase, where cells are preparing for M-phase (mitosis). Finally, in M-phase the DNA is separated and the cell divides into two identical cells. The length of the cell cycle varies between different cell lines mainly due to differences in the duration of G1-phase. Typically, for cultured human cell lines the G1-phase lasts for 3–24 h, S-phase 6–8 h, G2-phase 3–4 h, and M-phase about 1 h. The progression from one cell cycle phase to the next is tightly controlled and is driven by the activities of several Cyclin-CDK complexes, specific for each cell cycle transition.
Fig. 1

Cell cycle phases and major cyclin/CDK complexes of human cells. • G1-phase: Gap phase 1• S-phase: Synthesis phase (DNA is being duplicated)• G2-phase: Gap phase 2• M-phase: Mitosis (cell divides into two daugther cells)

It has long been known that radiosensitivity can be dependent on cell cycle phase (reviewed in Withers (1975a) and Pawlik and Keyomarsi (2004)). Experiments performed with irradiation of synchronized cells in vitro have shown that late S-phase cells are usually most radioresistant, while mitotic cells are most radiosensitive (Fig. 2) (Sinclair 1968). Notably, the difference in radiosensitivity between the most sensitive and resistant cell cycle phases can be as large as the difference in radiosensitivity for hypoxic versus normoxic cells (Fig. 2). The mechanisms explaining such cell cycle effects on radiosensitivity are not fully understood, but different use of repair pathways between the various cell cycle phases is likely involved. For instance, Homologous Recombination (HR) repair takes place in S- and G2-phase after DNA replication of the DNA strand is completed (Hustedt and Durocher 2016), which coincides with radioresistance in late S-phase. Indeed, experiments directly comparing the radiosensitivity of S/G2-phase populations from HR deficient versus HR proficient cells support that HR repair contributes to cause radioresistance in these cell cycle phases (Tamulevicius et al. 2007; Wilson et al. 2010). Moreover, mitotic cells are defective in DNA double strand break repair (Hustedt and Durocher 2016), coinciding with radiosensitivity.
Fig. 2

Variation in radiosensitivity throughout the cell cycle. Chinese hamster cells were synchronized in various cell cycle phases prior to irradiation: G1 (G1), early S (ES), late S (LS), M phase (M). Clonogenic survival versus radiation dose is shown (100 rads = 1 Gy). For comparison of the cell cycle effects to radioresistance caused by hypoxia, the stipled line marked ”M x 2.5” shows the expected clonogenic survival of M phase cells if they were irradiated at hypoxia. (Figure reprodced from (Sinclair 1968) with permission. © 2019 Radiation Research Society)

Cell cycle phase-dependent differences in radiosensitivity are considered important during clinical radiotherapy. One of the rationales described by the original four R’s of fractionated radiotherapy is “Redistribution” of tumor cells into more radiosensitive cell cycle phases (Withers 1975b). If some tumor cells are in a radioresistant cell cycle phase at the time of the first fraction, they may move into a more radiosensitive phase before the next fraction. In this way, all cycling tumor cells are most likely hit in a radiosensitive phase during a whole course of fractionated radiotherapy. In contrast, redistribution will not apply to noncycling normal cells, which is one reason why fractionation helps to improve therapeutic gain.

Furthermore, cell cycle phase effects on radiosensitivity can be important when radiotherapy is combined with chemotherapy or new targeted drugs. Drugs administrated several hours or days prior to irradiation may alter the cell cycle phase distribution and thereby cause radioresistance or radiosensitivity. For instance, drugs causing the tumor cells to accumulate in mitosis before irradiation will likely cause radiosensitivity (Milas et al. 1999). On the other hand, there may be no radiosensitizing effect if such drugs are added after irradiation. In some cases the same drug can even cause either radiosensitivity or radioresistance, depending on the treatment timing and resulting cell cycle effects. For example, an inhibitor of Polo-Like Kinase 1 caused mitotic accumulation and radiosensitization in cancer cell lines when added 1 day prior to radiation treatment, while it caused prolonged G2 checkpoint arrest and radioresistance if added at the same time as radiation (Lund-Andersen et al. 2014).

Cell Cycle and Radiation-Induced Cell Death: Irradiated Tumor Cells Most Often Die After Attempting Mitosis

A classic paradigm in radiobiology is that radiation causes so-called mitotic death (also called mitosis-linked death or mitotic catastrophe) (Hall and Giaccia 2006; Wouters 2009). This means that radiation does not kill the tumor cells right away but that cell death occurs at some point after the first mitosis following irradiation. The irradiated cells may undergo one, two, or a few divisions before they die hours or days later (Forrester et al. 1999).

Mitotic death is caused by chromosome damage occurring as a consequence of unrepaired or misrepaired radiation-induced DNA breaks. In the presence of such chromosome damage, problems arise in mitosis when the cell needs to separate the DNA to produce two identical daughter cells (Fig. 3, (Syljuåsen et al. 2004)). For instance, chromosome fragments lacking centromeres may not be incorporated into any of the two daughter nuclei, thereby causing micronucleus formation in the daughter cell cytoplasm. Also, chromosome damage may cause the genetic material to be unevenly distributed between the two nuclei of the daughter cells. Cell death will then occur at a later stage when a daughter cell is lacking an essential protein, due to lack of new protein production because the gene is missing in the nucleus (Brown and Attardi 2005). The exact mode of cell death occurring after the defective mitosis depends on which protein is lacking in the cells. Several death mechanisms can occur post mitosis, such as necrosis, apoptosis, autophagy, and senescence.
Fig. 3

Radiation-induced micronuclei formation occurs as a consequence of defective chromosome segregation in mitosis. (a) Live cell imaging of non-irradiated mitotic U2OS-H2B-GFP cells. U2OS osteosarcoma cells were transfected with histone H2B-GFP to visualize chromatin. Numbers indicate time (in minutes) relative to the first image in the series. (b) Live cell imaging of mitotic U2OS-H2B-GFP cells after irradiation (6 Gy). Cells were imaged between 40 and 50 hours after irradiation when they progressed through the first mitosis. Defective chromosome segregation is mainly due to radiation-induced chromosome damage (such as breaks, fragments, dicentrics, etc.). (Figure reproduced from (Syljuåsen et al. 2004))

Mitotic death is the most common way of radiation-induced cell death for all solid tumors and most of hematopoietic tumors. However, for some hematopoietic tumors and a few normal cell types, such as normal lymphocytes and thymocytes, radiation can induce rapid death in interphase (G1, S, and G2 phases) prior to mitosis. In the latter case, apoptosis is triggered due to activation of radiation-induced signaling cascades (Wouters 2009).

Cell Cycle Checkpoints Induced by Radiation

It is well known that radiation causes cells to transiently arrest the progression through the cell cycle (Iliakis et al. 2003). This arrest takes place at the so-called cell cycle checkpoints in G1, S, and G2 phases (Fig. 4). The G1 checkpoint prevents damaged cells from entering S-phase and is largely dependent on the tumor suppressor p53 and its downstream target p21 (Di Leonardo et al. 1994; Brugarolas et al. 1995). Radiation leads to activation of p53, which induces transcription of the CDK inhibitor p21, leading to inhibition of the Cyclin/CDK activity necessary to progress from G1 to S-phase. Notably, due to p53 mutations or other defects in the p53 pathway, the G1 checkpoint is most often lost or defective in tumor cells (Nagasawa et al. 1998; Syljuåsen et al. 1999). Defective G1 checkpoint control thus represents a major difference between cancer and normal cells. The S-phase checkpoint does not stop the cells at a specific point in the cell cycle but is manifested as reduced DNA replication during the whole S-phase. Irradiated cells are thus moving more slowly through S-phase. The S-phase checkpoint depends on the cell cycle kinase Wee1 and on radiation-induced activation of the ATR-Chk1 pathway (Sørensen et al. 2003; Beck et al. 2012). The G2 checkpoint halts the cells in late G2 phase and is the last checkpoint before cells enter mitosis. The G2 checkpoint is activated in both tumor and in cycling normal cells. Although the length varies between cell lines, a typical length of G2-arrest for human cells is about 2–3 h per Gy. Similar as for the S-phase checkpoint, activation of the G2 checkpoint requires the ATR-Chk1 and Wee1 pathways (Sanchez et al. 1997; Cliby et al. 1998; Liu et al. 2000; Wang et al. 2001; Zhao and Piwnica-Worms 2001). The immediate G2 checkpoint measured within the first couple of hours after irradiation is also dependent on ATM kinase, as the checkpoint is partly abrogated in cells lacking functional ATM. However, at later time points after radiation the checkpoint is ATM-independent and cells lacking ATM rather show a prolonged ATR/Chk1- dependent G2 checkpoint (Xu et al. 2002; Wang et al. 2003).
Fig. 4

Radiation-induced cell cycle checkpoints in G1, S, and G2 phases

The cell cycle checkpoints are important to provide time for DNA repair before cells are reaching mitosis. As discussed above, irradiated cancer cells often die via mitotic death. It is therefore critical whether or not the DNA damage is repaired prior to the first mitosis after radiation. Some repair pathways, such as HR and slow versions of Non-Homologous-End-Joining, take many hours to complete (Iliakis et al. 2004; Jeggo et al. 2011), and a few hours arrest at the cell cycle checkpoints can therefore make a difference in preventing mitotic death. Of note, arrest at the cell cycle checkpoints can also sometimes be permanent, thereby being a way of causing cell inactivation through senescence. Particularly, in normal fibroblasts radiation can induce permanent p53-dependent G1 arrest, which contributes to the cell inactivation of fibroblasts measured in clonogenic survival assays (Li et al. 1995; Tsang et al. 1995; Linke et al. 1997). However, after irradiation of fibroblasts with low doses such as 2 Gy, only a fraction of the cells will arrest permanently. A transient G1 arrest is observed in the remaining fraction, likely contributing to DNA repair.

Abrogation of the G2 Checkpoint as a Strategy for Tumor Radiosensitization

As mentioned above, a major difference between normal and tumor cells is that irradiated tumor cells often lack a normal G1 checkpoint. It was proposed that tumor cells lacking the G1 checkpoint may depend more on the S and G2 checkpoints for repair of the radiation damage compared to normal cells harboring an intact G1 checkpoint. Consequently, G2 checkpoint abrogation has been suggested as a strategy for tumor-selective radiosensitization (Fig. 5) (reviewed in (Dixon and Norbury 2002; Ma et al. 2011; Syljuåsen et al. 2015)). When the G2 checkpoint is abrogated after irradiation, normal cells can still arrest at the G1 checkpoint, which may support repair of the damage. However, p53 defective tumor cells will enter mitosis without having sufficient time for repair, and thereafter die via mitotic death. Notably, noncycling normal cells (in G0-phase) would also not be affected by G2 checkpoint abrogation. Early studies with drugs abrogating the G2 checkpoint, such as Caffeine, showed clear radiosensitizing effects (Busse et al. 1977; Russell et al. 1995). In order to obtain more clinically applicable drugs, several small molecule inhibitors of the ATR, Chk1, and Wee1 checkpoint kinases were developed over the past two decades (Pilie et al. 2019). Of note, such checkpoint kinase inhibitors will abrogate both the S and G2 checkpoints, and they can also affect other cellular responses such as DNA repair and replication (Syljuåsen et al. 2015). Interestingly, recent studies suggest that checkpoint kinase inhibitors can also influence anti-tumor immune responses after radiation (Vendetti et al. 2018; Dillon et al. 2019). A number of preclinical and clinical studies are currently exploring the effects of ATR, Chk1, and Wee1 inhibitors in combination with radiotherapy. These studies are carried out with different cancer cell types and the results will be interesting to follow in the next few years.
Fig. 5

The strategy of G2 checkpoint abrogation to obtain tumor-selective radiosensitization. Tumor cells lacking the p53-dependent G1 checkpoint are likely more dependent on the G2 checkpoint to survive after radiation compared to normal cells with an intact G1 checkpoint. When inhibitors of ATR, Chk1, or Wee1 kinases are added together with radiation treatment (IR), the G2 and S checkpoints are abrogated. Tumor cells lacking the G1 checkpoint have no remaining checkpoints and will enter mitosis and die via mitotic catastrophe. However, normal cells still have the G1 checkpoint that provides time for repair and will more likely survive


In conclusion, variation in tumor radiosensitivity between different cell cycle phases is one of the rationales behind fractionation in radiation therapy. Such variation in radiosensitivity can be important when radiotherapy is combined with drugs that alter the cell cycle phase distribution. Furthermore, the induction of cell cycle checkpoints in G1, S, and G2 phases is a major cellular effect of radiation. Notably, differences in the G1 checkpoint between normal and tumor cells may be exploited to obtain tumor-selective radiosensitization through G2 checkpoint abrogation. For this purpose, inhibitors of the ATR, Chk1, and Wee1 checkpoint kinases are currently being tested in combination with radiotherapy in preclinical and clinical studies.


  1. Beck H, Nahse-Kumpf V, Larsen MS, O'Hanlon KA, Patzke S, Holmberg C, Mejlvang J, Groth A, Nielsen O, Syljuåsen RG, Sørensen CS. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol Cell Biol. 2012;32(20):4226–36.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Brown JM, Attardi LD. The role of apoptosis in cancer development and treatment response. Nat Rev Cancer. 2005;5(3):231–7.PubMedCrossRefGoogle Scholar
  3. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995;377(6549):552–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Busse PM, Bose SK, Jones RW, Tolmach LJ. The action of caffeine on X-irradiated HeLa cells. II. Synergistic lethality. Radiat Res. 1977;71(3):666–77.PubMedCrossRefGoogle Scholar
  5. Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 1998;17(1):159–69.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Di Leonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994;8(21):2540–51.PubMedCrossRefGoogle Scholar
  7. Dillon MT, Bergerhoff KF, Pedersen M, Patin EC, Whittock H, Crespo-Rodriguez E, Pearson A, Paget JT, Smith HG, Patel RR, Foo S, Bozhanova G, Ragulan C, Fontana E, Desai K, Wilkins AC, Sadanandam A, Melcher A, McLaughlin M, Harrington KJ. ATR inhibition potentiates the radiation induced inflammatory tumour microenvironment. Clin Cancer Res. 2019;25(11):3392–403.PubMedCrossRefGoogle Scholar
  8. Dixon H, Norbury CJ. Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function. Cell Cycle. 2002;1(6):362–8.PubMedCrossRefGoogle Scholar
  9. Forrester HB, Vidair CA, Albright N, Ling CC, Dewey WC. Using computerized video time lapse for quantifying cell death of X-irradiated rat embryo cells transfected with c-myc or c-Ha-ras. Cancer Res. 1999;59(4):931–9.PubMedGoogle Scholar
  10. Hall EJ, Giaccia AJ. Radiobiology for the radiologist. Philadelphia: Lippincotts Williams & Wilkins; 2006.Google Scholar
  11. Hustedt N, Durocher D. The control of DNA repair by the cell cycle. Nat Cell Biol. 2016;19(1):1–9.PubMedCrossRefGoogle Scholar
  12. Iliakis G, Wang Y, Guan J, Wang H. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene. 2003;22(37):5834–47.PubMedCrossRefGoogle Scholar
  13. Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G. Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res. 2004;104(1–4):14–20.PubMedCrossRefGoogle Scholar
  14. Jeggo PA, Geuting V, Lobrich M. The role of homologous recombination in radiation-induced double-strand break repair. Radiother Oncol. 2011;101(1):7–12.PubMedCrossRefGoogle Scholar
  15. Li C, Nagasawa H, Tsang N, Little J. Radiation-induced irreversible g(0) g(1) block is abolished in human-diploid fibroblasts transfected with the human papilloma-virus e6 gene – implication of the p53-cip1 waf1 pathway. Int J Oncol. 1995;6(1):233–6.PubMedGoogle Scholar
  16. Linke SP, Clarkin KC, Wahl GM. p53 mediates permanent arrest over multiple cell cycles in response to gamma-irradiation. Cancer Res. 1997;57(6):1171–9.PubMedGoogle Scholar
  17. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000;14(12):1448–59.PubMedPubMedCentralGoogle Scholar
  18. Lund-Andersen C, Patzke S, Nahse-Kumpf V, Syljuåsen RG. PLK1-inhibition can cause radiosensitization or radioresistance dependent on the treatment schedule. Radiother Oncol. 2014;110(2):355–61.PubMedCrossRefGoogle Scholar
  19. Ma CX, Janetka JW, Piwnica-Worms H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med. 2011;17(2):88–96.PubMedCrossRefGoogle Scholar
  20. Milas L, Milas MM, Mason KA. Combination of taxanes with radiation: preclinical studies. Semin Radiat Oncol. 1999;9(2 Suppl 1):12–26.PubMedGoogle Scholar
  21. Nagasawa H, Keng P, Maki C, Yu Y, Little JB. Absence of a radiation-induced first-cycle G1-S arrest in p53+ human tumor cells synchronized by mitotic selection. Cancer Res. 1998;58(9):2036–41.PubMedGoogle Scholar
  22. Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59(4):928–42.PubMedCrossRefGoogle Scholar
  23. Pilie PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16(2):81–104.PubMedCrossRefGoogle Scholar
  24. Russell KJ, Wiens LW, Demers GW, Galloway DA, Plon SE, Groudine M. Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res. 1995;55(8):1639–42.PubMedGoogle Scholar
  25. Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science. 1997;277(5331):1497–501.PubMedCrossRefGoogle Scholar
  26. Sinclair WK. Cyclic x-ray responses in mammalian cells in vitro. Radiat Res. 1968;33(3):620–43.PubMedCrossRefGoogle Scholar
  27. Sørensen CS, Syljuåsen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell. 2003;3(3):247–58.PubMedCrossRefGoogle Scholar
  28. Syljuåsen RG, Krolewski B, Little JB. Loss of normal G1 checkpoint control is an early step in carcinogenesis, independent of p53 status. Cancer Res. 1999;59(5):1008–14.PubMedGoogle Scholar
  29. Syljuåsen RG, Sørensen CS, Nylandsted J, Lukas C, Lukas J, Bartek J. Inhibition of Chk1 by CEP-3891 accelerates mitotic nuclear fragmentation in response to ionizing radiation. Cancer Res. 2004;64(24):9035–40.PubMedCrossRefGoogle Scholar
  30. Syljuåsen RG, Hasvold G, Hauge S, Helland A. Targeting lung cancer through inhibition of checkpoint kinases. Front Genet. 2015;6:70.PubMedPubMedCentralGoogle Scholar
  31. Tamulevicius P, Wang M, Iliakis G. Homology-directed repair is required for the development of radioresistance during S phase: interplay between double-strand break repair and checkpoint response. Radiat Res. 2007;167(1):1–11.PubMedCrossRefGoogle Scholar
  32. Tsang NM, Nagasawa H, Li C, Little JB. Abrogation of p53 function by transfection of HPV16 E6 gene enhances the resistance of human diploid fibroblasts to ionizing radiation. Oncogene. 1995;10(12):2403–8.PubMedGoogle Scholar
  33. Vendetti FP, Karukonda P, Clump DA, Teo T, Lalonde R, Nugent K, Ballew M, Kiesel BF, Beumer JH, Sarkar SN, Conrads TP, O'Connor MJ, Ferris RL, Tran PT, Delgoffe GM, Bakkenist CJ. ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. J Clin Invest. 2018;128(9):3926–40.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, Sun Y. Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res. 2001;61(22):8211–7.PubMedGoogle Scholar
  35. Wang X, Khadpe J, Hu B, Iliakis G, Wang Y. An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells. J Biol Chem. 2003;278(33):30869–74.PubMedCrossRefGoogle Scholar
  36. Wilson PF, Hinz JM, Urbin SS, Nham PB, Thompson LH. Influence of homologous recombinational repair on cell survival and chromosomal aberration induction during the cell cycle in gamma-irradiated CHO cells. DNA Repair (Amst). 2010;9(7):737–44.CrossRefGoogle Scholar
  37. Withers HR. Cell cycle redistribution as a factor in multifraction irradiation. Radiology. 1975a;114(1):199–202.PubMedCrossRefGoogle Scholar
  38. Withers HR. The four R’s of radiotherapy. Adv Radiat Biol. 1975b;5:241–71.CrossRefGoogle Scholar
  39. Wouters BG. Cell death after irradiation: how, when and why cells die. In: Joiner M, Van der Kogel A, editors. Basic clinical radiobiology 2009. London: Hodder Arnold; 2009. p. 23–40.Google Scholar
  40. Xu B, Kim ST, Lim DS, Kastan MB. Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol Cell Biol. 2002;22(4):1049–59.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Zhao H, Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol. 2001;21(13):4129–39.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium HospitalOslo University HospitalOsloNorway

Personalised recommendations