Read some article that stem cell could repair themselves and the capability is encoded in the DNA and UV could induce the process in vitro. Wondering there is any new studies on these DNA repair capability in CML and how to trigger the DNA repair gene....? Any information worth sharing ?
DNA repair capability in stem cell ?
Posted 20 February 2011 - 12:09 PM
Several lines of evidence suggest involvement of both Bcr and Abl in DNA damage response. For instance, the SH3 domain of Abl binds residues 1373-1382 of the ATM product (26) . After ionizing radiation, the Atm kinase phosphorylates Abl; in cells from ataxia telangectasia patients (known to be sensitive to radiation damage), this interaction fails to occur (26 , 27) . Bcr has also been linked to the DNA repair process, albeit via pathways distinct from those associated with Abl. Indeed, Bcr as well as Bcr-Abl bind to the XPB/ERCC3 protein (23 , 24) , a subunit of the basal transcription factor TFIIH and a critical player in the UV-induced NER process (reviewed in Ref. 47 ). Mutations in XPB induce a profound human DNA repair disorder characterized by numerous skin tumors after UV exposure (reviewed in Ref. 25 ). Although XPB is a nuclear protein and Bcr was initially believed to be localized exclusively in the cytoplasm (15 , 21 , 48) , it has now been demonstrated that Bcr can also be found in the nucleus in close association with condensed chromatin (21 , 22) . Furthermore, it has been claimed that even a small fraction of Bcr-Abl can be discerned in the nucleus (24) . On the basis of these data, we sought to determine the effect of UVC on DNA repair processes in cells stably transfected with BCR-ABL versus their parental counterparts.
Our initial hypothesis was that the presence of BCR-ABL would attenuate the DNA repair process and thus account for the genomic instability that characterizes CML and leads to clonal evolution and blast crisis. The experimental data in this area are still extremely sparse and not all of it is supportive. Indeed, in the only study to examine the impact of BCR-ABL on UV-related DNA repair, Takeda et al. (24) demonstrated that when XPB is coexpressed with transfected p210BCR-ABL, the XPB protein is heavily phosphorylated on its tyrosine residues and is unable to correct a UVC-related DNA repair defect in XPB-null mutants. On the other hand, transfection of BCR-ABL into cells carrying the wild-type XPB gene did not substantially impair DNA repair (24) .
Contrary to our expectations, our initial experiments using the Comet assay demonstrated that the DNA repair incision process was enhanced in both hematopoietic cells and fibroblasts transfected with BCR-ABL as compared with parental controls (Fig. 1<$REFLINK> and data not shown). More vigorous DNA repair (longer comet tails) were consistently evident for 3 h after UVC exposure. In addition, there was more rapid completion of the DNA repair process at 24 h. To verify these results, a RIA that specifically measures CPDs was used. This assay showed substantially less DNA damage induced by equivalent doses, as well as more rapid NER in BCR-ABL-positive hematopoietic cells as compared with their parental counterparts (Fig. 3, A and B)<$REFLINK> . Because the BCR-ABL-transformed cells and the parental cells (grown in the presence of growth factor) had similar proliferative rates and cell cycle distribution (as determined by FACS; data not shown), these factors could not account for the differences in DNA repair and damage. Finally, the demonstration of increased post-UVC survival of the BCR-ABL-positive cells in clonogenic assays confirmed their enhanced UVC resistance. (These results, although interesting, do not necessarily imply a functional interaction between BCR-ABL and XPB).
The effects of UV, ?-radiation, and cytotoxic drugs on DNA may be substantially different, at least partly because of distinct DNA repair pathways associated with each treatment. Several investigators have examined the impact of BCR-ABL on the sequelae of ionizing radiation. Santucci et al. (29) demonstrated that after ?-irradiation, BCR-ABL-positive cells show decreased survival in clonogenic assays as compared with the BCR-ABL-negative controls. They therefore suggested that BCR-ABL either amplified ?-irradiation-induced DNA damage or inhibited the DNA repair process. Deutsch et al. (30) demonstrated down-regulation of a major DNA double-strand break repair protein (DNA-PK) and induction of a DNA repair defect (as measured by fluorescent in situ hybridization) in BCR-ABL-positive cells. However, Bedi et al. (31) reported that the rate of DNA repair in BCR-ABL-positive cells was not different from that of the controls after ionizing radiation. Furthermore, Slupianek et al. (32) showed that Bcr-Abl enhanced expression and phosphorylation of RAD51, a key player in the repair of drug- and ?-irradiation-induced double-strand breaks (49) , and increased recombination repair after exposure to cytotoxic drugs. All of these authors reported that BCR-ABL-bearing cells are resistant to ?-irradiation-induced apoptosis and/or are drug-resistant as compared with their BCR-ABL-negative parental counterparts (29, 30, 31, 32) . We also found significantly reduced apoptosis in the BCR-ABL-positive cells after UVC exposure (Fig. 2)<$REFLINK> . Hence, diminished programmed cell death in BCR-ABL-bearing cells is seen after a variety of insults, including ionizing radiation, UVC, and cytotoxic drugs (29, 30, 31, 32) . The mechanisms mediating resistance to programmed cell death in BCR-ABL-positive cells may include induction of antiapoptotic genes such as BCL-2 and BCL-xL (50 , 51) , inhibition of proapoptotic proteins such as Bad (52) , up-regulation of cytoprotective signaling pathways, including signal transducers and activators of transcription 5, Akt, nuclear factor-?B (53, 54, 55, 56) , as well as prolonged cell cycle arrest at the G2-M checkpoint to allow the cells sufficient time to repair DNA damage (31) . In addition, increased resistance to DNA damage and enhanced DNA repair may account for the diminished apoptosis after UVC or chemotherapy exposure.
In conclusion, we demonstrate that in response to UVC irradiation, p210BCR-ABL confers resistance to overt UV damage and accelerates the DNA repair rate. Increased DNA repair may or may not play a key functional role in resistance of Bcr-Abl-bearing cells to DNA damage. These changes are accompanied by a marked diminution in UVC-induced apoptosis. Our results are analogous to those reported by Slupianek et al. (32) , who demonstrated that Bcr-Abl facilitates RAD51-associated homologous recombination repair of DNA double-strand breaks occurring after exposure to cytotoxic agents and hence induces drug resistance. Taken together, the literature suggests that Bcr-Abl profoundly alters the response to DNA injury, albeit with different effects depending on the genotoxic trigger and which of several repair pathways are investigated (57) . The potential leukemogenic effects of DNA damage from ionizing radiation are well recognized, and recent results of both epidemiological studies and animal models implicate UV irradiation in augmentation of internal lymphoid malignancies (58 , 59) . Therefore, a role for a BCR-ABL-related alteration in DNA repair in the genomic instability leading to blast crisis may be postulated (24 , 29 , 30) . Superficially, it would appear that more efficient DNA repair would be incompatible with such a role. It is, however, conceivable that this interplay is complex and that more hurried repair may, in the long run, be accompanied by subtle errors in the process. Furthermore, the resistance to apoptosis that is conferred on these cells may make them susceptible to the eventual emergence of aberrations. In the presence of double-strand breaks, it has been previously shown that lack of repair leads to programmed cell death, whereas incorrect repair may lead to chromosomal loss or translocation (60) . Progression in CML is driven by the slow accumulation of molecular genetic aberrations that, although inevitable, occurs over a period of years. Additional studies are needed to determine to what extent facilitated but unfaithful repair exists in CML and if such a phenomenon coupled with a stalled apoptotic program may, in the long term, impact genomic integrity in this disorder.
Posted 21 February 2011 - 12:50 PM
Not surprisingly, I disagree....
CML is actually an "epigenetic" disease as it is not genetically inherited. It is caused by environmental stresses, such as exposure to radiation (x-rays, etc) Benzene, and other sources.
A good starting place to learn about epigenetics:
The next link from Discover magazine highlights some important work going on at McGill University in Montreal in the area of epigenetics and the title is "DNA is not Destiny"....
So, I do not think we can answer the question Yes or No at this time...
Posted 21 February 2011 - 06:38 PM
VC asked a different question. He asked whether, once a cell becomes translocated with t(9,22), can it become normal again. Sorry, no.
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