PML-dependent mechanisms of DNA-damage repair — opportunities for a new laboratory diagnostic method for evaluating the chemo- and radiosensitivity of malignant neoplasms
S.V. BOYCHUK1,2, O. GJOERUP2
1Kazan State Medical University, 49 Butlerova St., Kazan, Russian Federation 420012
2University of Pittsburgh Cancer Institute, Hillman Cancer, Research Pavilion, Suite 1.4 5117 Centre Ave, Pittsburgh, PA, 15213 USA
Boychuk S.V. — D. Med. Sc., Professor, Head of Department of Pathophysiology, phone: (843) 236-75-31, e-mail: boichuksergei@mail.ru1,2
Gjoerup Ole — Doctor of Biological Sciences, chief of laboratory of virus oncology, (412) 623-77-07, e-mail: ogv27@pitt.edu2
It was found that in terms of PML protein knockdown against the background of DNA damage, caused by chemotherapeutic agents (doxorubicin, etoposide and etc.) and radiation, happens abnormality of focal distribution of proteins which participate in DNA damages reparation by a mechanism of homologous recombination. This allows us to consider malignant neoplasms with reduced PML protein expression as potentially susceptible to chemotherapy and radiotherapy. Development of laboratory diagnostic method of chemo-and radiosensitivity of malignant tumors, based on an assessment of the ability of tumor cells to repair DNA damage, caused by chemotherapy and ionizing radiation, seems promising and will provide the right choice of tactics in the process of the patient-specific therapy of oncologic patients, as well as follow-up monitoring of its effectiveness.
Key words: DNA-damage repair, homologous recombination, PML protein, chemo- and radiosensitivity of a tumor, laboratory diagnostics.
REFERENCES
1. Claus E.B., Schildkraut J.M., Thompson W.D., Risch N.J. The genetic attributable risk of breast and ovarian cancer. Cancer, 1996, no. 77, pp. 2318-2324.
2. Stratton M.R., Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet., 2008, no. 40, pp. 17-22.
3.Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J. Identification of the breast cancer susceptibility gene BRCA2. Nature, 1995, no. 378, pp. 789-792.
4. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P.A., Harshman K., Tavtigian S. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 1994, no. 266, pp. 66-71.
5. Audeh M.W., Carmichael J., Penson R.T. Oral poly (ADP-ribose)-polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet, 2010, no. 376 (9737), pp. 245-251.
6. Kummar S., Chen A., Parchment R.E. Advances in using PARP Inhibitors to treat cancer. BMC Medicine, 2012, no. 10 (25), pp. 1-5.
7. Penning T.D., Zhu G.D., Gandhi V.B. Discovery of the poly(ADP-ribose)-polymerase (PARP) inhibitor 2-[(R)-2-methyl pyrrolid in-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J. Med. Chem., 2009, no. 52, pp. 514-523.
8. Bernardi R., Pandolfi P.P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol., 2007, no. 8, pp. 1006-1016.
9. Dellaire G., Ching R.W., Ahmed K., Jalali F., Tse K.C. Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR. J Cell Biol., 2006, no. 175, pp. 55-66.
10. Boichuk S.V., Hu L., Makielski K. Functional connection between Rad51 and PML in homology-directed repair. PloS One, 2011, no. 6 (10), pp. 1-13.
11. Rogakou E.P., Pilch D.R., Orr A.H. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem., 1998, no. 273 (10), pp. 5858-5868.
12. Bakkenist C.J., Kastan M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 2003, no. 421 (6922), pp. 499-506.
13. Gurrieri C., Capodieci P., Bernardi R. et al. Loss of tumor suppressor PML in human cancers of multiple histologic origins. J. Nat. Cancer Inst., 2004, no. 96, pp. 269-279.
14. Boychuk S.V. Ramazanov B.R., Mustafin I.G. Dzhoerap O. Increased activity of poly ( ADP- ribose) polymerase in the conditions of protein knockdown PML – new perspectives cancer therapy. Kazanskiy meditsinskiy zhurnal, 2013, no. 1, pp. 75-79 (in Russ.)