Can I get help on drawing a mechanism for the paragraph below? p53 stabilization by IR The signal upstream of p53 stabilization and activation after IR exposure most likely originate from DNA DSBs. This is supported by the fact that the kinases implicated in the phosphorylation of p53 are also implicated in DSB repair. These include two kinases that belong to the PI-3 kinase family, DNA-PK and ATM (see above), and indirectly, the checkpoint kinase 2 (Chk2). Ser15 of p53 was identified as a substrate for DNA-PK in vitro (Lees-Miller et al., 1992). Since DNA-PK is required for DSB repair in mammalian cells after IR exposure and since this residue falls within the MDM2-binding domain of the protein, this was an attractive model of p53 stabilization after IR. However, several recent reports have shown that Ser15 of p53 is phosphorylated in cells deficient in DNA-PK and that p53 accumulation in these cells is capable of generating cell cycle arrest or apoptosis after IR (Abraham et al., 1999; Araki et al., 1999; Jimenez et al., 1999). ATM is another kinase that has been shown to phosphorylate Ser15 in response to DNA damage induced by IR in vitro (Banin et al., 1998; Canman et al., 1998). In contrast to DNA-PK-deficient cells, AT lymphoblasts that lack the ATM gene have a decreased ability to generate p53-dependent cell cycle arrest or apoptosis after IR, suggesting an important role for ATM in generating these responses in vivo. Additionally, ATM has been implicated in phosphorylating Ser9 and Ser46 directly and Ser20 indirectly through Chk2 (Ahn et al., 2000; Hirao et al., 2000). Interestingly, ATM has also been implicated as the kinase that phosphorylates MDM2, thus disrupting the p53-MDM2 interaction by phosphorylation of both of these proteins.
Can I get help on drawing a mechanism for the paragraph below?
p53 stabilization by IR
The signal upstream of p53 stabilization and activation after IR exposure most likely originate from DNA DSBs. This is supported by the fact that the kinases implicated in the phosphorylation of p53 are also implicated in DSB repair. These include two kinases that belong to the PI-3 kinase family, DNA-PK and ATM (see above), and indirectly, the checkpoint kinase 2 (Chk2). Ser15 of p53 was identified as a substrate for DNA-PK in vitro (Lees-Miller et al., 1992). Since DNA-PK is required for DSB repair in mammalian cells after IR exposure and since this residue falls within the MDM2-binding domain of the protein, this was an attractive model of p53 stabilization after IR. However, several recent reports have shown that Ser15 of p53 is phosphorylated in cells deficient in DNA-PK and that p53 accumulation in these cells is capable of generating cell cycle arrest or apoptosis after IR (Abraham et al., 1999; Araki et al., 1999; Jimenez et al., 1999). ATM is another kinase that has been shown to phosphorylate Ser15 in response to DNA damage induced by IR in vitro (Banin et al., 1998; Canman et al., 1998). In contrast to DNA-PK-deficient cells, AT lymphoblasts that lack the ATM gene have a decreased ability to generate p53-dependent cell cycle arrest or apoptosis after IR, suggesting an important role for ATM in generating these responses in vivo. Additionally, ATM has been implicated in phosphorylating Ser9 and Ser46 directly and Ser20 indirectly through Chk2 (Ahn et al., 2000; Hirao et al., 2000). Interestingly, ATM has also been implicated as the kinase that phosphorylates MDM2, thus disrupting the p53-MDM2 interaction by phosphorylation of both of these proteins.
p53 is a transcription factor protein that is responsible to arresting the cell cycle in cells with DNA damage. Based on the level of damage, p53 could either aid in DNA repair (low DNA damage) or induce apoptosis (high DNA damage).p53 in its inactive latent form is found bound to another protein called MDM2 (Murine Double Minute 2) forming the p53-MDM2 Complex. Upon DNA damage, like DNA DSB (DNA Double Strand Break), certain kinases inside the nucleus are activated to phosphorylate both the p53 and MDM2. p53 phosphorylation at 3 sites near the N-terminal was observed crucial, all these sites were serine residues Ser15, Ser20 and Ser46. Ser 15 can be phosphorylated by either ATM(Atexia Telangiectasia Mutated), ATR (Atexia Telangiectasia Mutated & Rad3 related), ChK1( Checkpoint Kinase 1) or DNA-PK(DNA Protein Kinase).Ser20 can be phosphorylated by ChK2 or PI3(Polo Like Kinase 3). Ser 46 can be phosphorylated by HIP K2 or PKC delta. MDM2 is phosphorylated at multiple sites by ATM. Upon phosphorylation, the p53 and MDM2 dissociates from each other. This phosphorylation (also acetylation which is not discussed here) stabilizes p53 and p53 starts to accumulate inside the nucleus. P53 acts on the DSB and either aids in its repair (if the damage was little and deemed repairable ) or induces cell apoptosis (if the damage was too much and beyond repair).
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