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Microhomologous connection of the ends

Microhomologous termination (MSC) , also known as alternative non-homologous termination (Alt- NSC ), is one way of repairing double-strand breaks in the DNA chain . As discussed by McVeigh and Lee, [1] the main distinguishing feature of MSCs is the use of microhomologous sequences consisting of 5–25 base pairs (bp) MSCs are often associated with chromosomal abnormalities, such as deletions, translocations, inversions, and other complex rearrangements.

There are two other types of DNA repair: homologous recombination (GR) and non-homologous junction of the ends (NSC). But only MSCs in the process of repairing use the microhomologous sequences necessary for aligning sections of the molecule on both sides from the rupture to their direct connection. MSCs use Ku-protein and DNA-PC-dependent repair mechanism (DNA-PC is a DNA-dependent protein kinase, a protein from the class of transferases), and the repair itself occurs during the S-phase of the cell cycle, in contrast to G0 / G1 and early S-phases during NSC, and during late S- and G-phases during GR.

MSC works by ligating incompatible overhanging sections of the DNA chain, removing the corresponding nucleotides and filling in the lost base pairs. When a break occurs, the homology of the above sequences of 5-25 base pairs in length is used as a basis for aligning the chain on either side of the break. After alignment, any protruding sections of the chain are removed, and the missing nucleotides are inserted. Since this repair path does not take into account the lost base pairs, but simply cuts out the damaged parts and connects the DNA strands to one another, it often leads to deletion of significant DNA fragments.

Based on the foregoing, it is clear that MSCs are a error prone method. Deletion of DNA can lead to oncogenes and play a role in the development of cancer. In most cases, a cell uses MSCs only when the other two repair methods are unavailable or undesirable for any reason.

Content

Genes Needed for MSCs

Biochemical analysis shows that there are at least 6 genes necessary for the course of this type of repair: FEN1, LIG3, MRE11 , NBS1 , PARP1 and XRCC1. [2] All six of these genes are actively expressed during the course of several types of cancer.

MSCs and Cancer

The work of FEN1 is actively expressed in most cases of breast cancer, [3] prostate, [4] stomach, [5] [6] neuroblastoma, [7] pancreas, [8] lungs. [9]

LIG3 is associated with chronic myelogenous leukemia, [10] multiple myeloma [11], and breast cancer. [12]

MRE11 is overly expressed in breast cancer. [13]

NBS1 is expressed in prostate cancer, [14] , head and neck tumors, [15] and also during squamous cell carcinoma of the oral cavity. [sixteen]

PARP1 is active in leukemia caused by BCR-ABL tyrosine kinase activity, [17] with neuroblastoma, [18] with testicular cancer and germ cell tumors [19] and with Ewing sarcoma, [20]

XRCC1 is overexpressed during non-small cell lung carcinoma (NLC) , [21] and even more strongly in metastatic lymph nodes of the NLC. [22] Perhaps the XRCC1 expression deficit, which suppresses tumor growth, is even more interesting, as revealed by experiments on the induction of three types of cancer in mice (colon cancer, melanoma, and breast cancer). [23]

MSCs are a mutagenic repair pathway, since they always lead to small deletions. [24] From this point of view, NSCs and GRs are much more accurate and efficient. [25] Which method will be chosen by the cell to repair a double-stranded break in DNA is determined by many factors. When the FEN1, Ligase III, MRE11, NBS1, PARP1 or XRCC1 genes are overexpressed (with FEN1 because its promoter is hypomelated), an inaccurate MSC method may be more preferable as causing a high level of mutations and increasing the risk of cancer.

In tumors, there is often insufficient expression of one or more DNA repair genes, however, excessive expression of DNA repair genes is less common. For example, at least 36 DNA repair enzymes, when they are mutationally defective in germline cells, cause an increased risk of developing hereditary cancer syndromes. [26] (see also DNA repair-deficiency disorder.) Similarly, expression of at least 12 DNA repair genes is often epigenetically suppressed during certain cancers. (See also Epigenetically reduced DNA repair and cancer.) As a rule, insufficient expression of repair genes leads to an increase in the number of damages in the DNA chain, and therefore increases the likelihood of developing cancer, however, if the MSC pathway for DNA repair is used, already excessive expression of FEN1 genes, LIGIII, MRE1, PARP1, NBS1 and XRCC1 can lead to cancer, because, as already mentioned, MSCs are a fairly mutagenic method. This is confirmed by observations during which the suppression of the mutagenic protein XRCC1 (involved in DNA repair and complexing with the LIGIII protein) led to a decrease in cancer progression.

Links

  1. ↑ McVey M., Lee SE MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings (eng.) // Trends Genet. : journal. - 2008 .-- Vol. 24 , no. 11 . - P. 529-538 . - DOI : 10.1016 / j.tig.2008.08.08.007 . - PMID 18809224 .
  2. ↑ Sharma S., Javadekar SM, Pandey M., Srivastava M., Kumari R., Raghavan SC Homology and enzymatic requirements of microhomology-dependent alternative end joining (English) // Cell Death Dis: journal. - 2015. - Vol. 6 . - P. e1697 . - DOI : 10.1038 / cddis.2015.58 . - PMID 25789972 .
  3. ↑ Singh P., Yang M., Dai H., Yu D., Huang Q., Tan W., Kernstine KH, Lin D., Shen B. Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers .) // Mol. Cancer Res. : journal. - 2008. - Vol. 6 , no. 11 . - P. 1710-1717 . - DOI : 10.1158 / 1541-7786.MCR-08-0269 . - PMID 19010819 .
  4. ↑ Lam JS, Seligson DB, Yu H., Li A., Eeva M., Pantuck AJ, Zeng G., Horvath S., Belldegrun AS Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score .) // BJU Int. : journal. - 2006. - Vol. 98 , no. 2 . - P. 445-451 . - DOI : 10.1111 / j.1464-410X.2006.06224.x . - PMID 16879693 .
  5. ↑ Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells (eng.) // Clin. Cancer Res. : journal. - 2005. - Vol. 11 , no. 2 Pt 1 . - P. 473-482 . - PMID 15701830 .
  6. ↑ Wang K., Xie C., Chen D. Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis (Eng.) // Int. J. Mol. Med. : journal. - 2014 .-- Vol. 33 , no. 5 . - P. 1268-1274 . - DOI : 10.3892 / ijmm.2014.1682 . - PMID 24590400 .
  7. ↑ Krause A., Combaret V., Iacono I., Lacroix B., Compagnon C., Bergeron C., Valsesia-Wittmann S., Leissner P., Mougin B., Puisieux A. Genome-wide analysis of gene expression in neuroblastomas detected by mass screening // Cancer Lett. : journal. - 2005. - Vol. 225 , no. 1 . - P. 111-120 . - DOI : 10.1016 / j.canlet.2004.10.0.035 . - PMID 15922863 .
  8. ↑ Iacobuzio-Donahue CA, Maitra A., Olsen M., Lowe AW, van Heek NT, Rosty C., Walter K., Sato N., Parker A., ​​Ashfaq R., Jaffee E., Ryu B., Jones J., Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays (Eng.) // Am. J. Pathol. : journal. - 2003. - Vol. 162 , no. 4 . - P. 1151-1162 . - DOI : 10.1016 / S0002-9440 (10) 63911-9 . - PMID 12651607 .
  9. ↑ Nikolova T., Christmann M., Kaina B. FEN1 is overexpressed in testis, lung and brain tumors (English) // Anticancer Res. : journal. - 2009. - Vol. 29 , no. 7 . - P. 2453-2459 . - PMID 19596913 .
  10. ↑ Sallmyr A., ​​Tomkinson AE, Rassool FV Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks (Eng.) // Blood : journal. - American Society of Hematology 2008. - Vol. 112 , no. 4 . - P. 1413-1423 . - DOI : 10.1182 / blood-2007-07-104257 . - PMID 18524993 .
  11. ↑ Herrero AB, San Miguel J., Gutierrez NC Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability (English) // PLoS ONE : journal. - 2015. - Vol. 10 , no. 3 . - P. e0121581 . - DOI : 10.1371 / journal.pone.0121581 . - PMID 25790254 .
  12. ↑ Tobin LA, Robert C., Nagaria P., Chumsri S., Twaddell W., Ioffe OB, Greco GE, Brodie AH, Tomkinson AE, Rassool FV Targeting abnormal DNA repair in therapy-resistant breast cancers // Mol. Cancer Res. : journal. - 2012. - Vol. 10 , no. 1 . - P. 96-107 . - DOI : 10.1158 / 1541-7786.MCR-11-0255 . - PMID 22112941 .
  13. ↑ Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, Lo S. Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer (Eng.) // J. Natl. Cancer Inst. : journal. - 2012. - Vol. 104 , no. 19 . - P. 1485-1502 . - DOI : 10.1093 / jnci / djs355 . - PMID 22914783 .
  14. ↑ Berlin A., Lalonde E., Sykes J., Zafarana G., Chu KC, Ramnarine VR, Ishkanian A., Sendorek DH, Pasic I., Lam WL, Jurisica I., van der Kwast T., Milosevic M. , Boutros PC, Bristow RG NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer (Eng.) // Oncotarget : journal. - 2014 .-- Vol. 5 , no. 22 . - P. 11081-11090 . - DOI : 10.18632 / oncotarget.2404 . - PMID 25415046 .
  15. ↑ Yang MH, Chiang WC, Chou TY, Chang SY, Chen PM, Teng SC, Wu KJ Increased NBS1 expression is a marker of aggressive head and neck cancer and overexpression of NBS1 contributes to transformation (Eng.) // Clin. Cancer Res. : journal. - 2006. - Vol. 12 , no. 2 . - P. 507-515 . - DOI : 10.1158 / 1078-0432.CCR-05-1231 . - PMID 16428493 .
  16. ↑ Hsu DS, Chang SY, Liu CJ, Tzeng CH, Wu KJ, Kao JY, Yang MH Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity // Cancer Sci. : journal. - 2010 .-- Vol. 101 , no. 4 . - P. 1029-1037 . - DOI : 10.1111 / j.1349-7006.2009.01471.x . - PMID 20175780 .
  17. ↑ Muvarak N., Kelley S., Robert C., Baer MR, Perrotti D., Gambacorti-Passerini C., Civin C., Scheibner K., Rassool FV c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors , LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias (Eng.) // Mol. Cancer Res. : journal. - 2015. - Vol. 13 , no. 4 . - P. 699-712 . - DOI : 10.1158 / 1541-7786.MCR-14-0422 . - PMID 25828893 .
  18. ↑ Newman EA, Lu F., Bashllari D., Wang L., Opipari AW, Castle VP Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma (Eng.) // Mol. Cancer Res. : journal. - 2015. - Vol. 13 , no. 3 . - P. 470-482 . - DOI : 10.1158 / 1541-7786.MCR-14-0337 . - PMID 25563294 .
  19. ↑ Mego M., Cierna Z., Svetlovska D., Macak D., Machalekova K., Miskovska V., Chovanec M., Usakova V., Obertova J., Babal P., Mardiak J. PARP expression in germ cell tumors (English) // J. Clin. Pathol. : journal. - 2013 .-- Vol. 66 , no. 7 . - P. 607-612 . - DOI : 10.1136 / jclinpath-2012-201088 . - PMID 23486608 .
  20. ↑ Newman RE, Soldatenkov VA, Dritschilo A., Notario V. Poly (ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells (Eng.) // Oncol. Rep. : journal. - 2002. - Vol. 9 , no. 3 . - P. 529-532 . - DOI : 10.3892 / or.9.3.529 . - PMID 11956622 .
  21. ↑ Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S., Sung SW, Kim JH The prognostic significance of ERCC1, BRCA1, XRCC1, and betaIII-tubulin expression in patients with non-small cell lung cancer treated by platinum- and taxane-based neoadjuvant chemotherapy and surgical resection (English) // Lung Cancer: journal. - 2010 .-- Vol. 68 , no. 3 . - P. 478-483 . - DOI : 10.1016 / j.lungcan.2009.07.004 . - PMID 19683826 .
  22. ↑ Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S., Sung SW, Kim JH Differences in the expression profiles of excision repair crosscomplementation group 1, x-ray repair crosscomplementation group 1, and betaIII-tubulin between primary non-small cell lung cancer and metastatic lymph nodes and the significance in mid-term survival (Eng.) // J Thorac Oncol : journal. - 2009. - Vol. 4 , no. 11 . - P. 1307-1312 . - DOI : 10.1097 / JTO.0b013e3181b9f236 . - PMID 19745766 .
  23. ↑ Pettan-Brewer C., Morton J., Cullen S., Enns L., Kehrli KR, Sidorova J., Goh J., Coil R., Ladiges WC Tumor growth is suppressed in mice expressing a truncated XRCC1 protein ) // Am J Cancer Res : journal. - 2012. - Vol. 2 , no. 2 . - P. 168-177 . - PMID 22432057 .
  24. ↑ Liang L., Deng L., Chen Y., Li GC, Shao C., Tischfield JA Modulation of DNA end joining by nuclear proteins (Eng.) // J. Biol. Chem. : journal. - 2005. - Vol. 280 , no. 36 . - P. 31442-31449 . - DOI : 10.1074 / jbc.M503776200 . - PMID 16012167 .
  25. ↑ Ottaviani D., LeCain M., Sheer D. The role of microhomology in genomic structural variation (Eng.) // Trends Genet. : journal. - 2014 .-- Vol. 30 , no. 3 . - P. 85-94 . - DOI : 10.1016 / j.tig.2014.01.01.001 . - PMID 24503142 .
  26. ↑ Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013).

Links

  • MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings
  • DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining
  • Distinctive differences in DNA double-strand break repair between normal urothelial and urothelial carcinoma cells
Source - https://ru.wikipedia.org/w/index.php?title= Microhomologous_terminal_connection&oldid = 101064498


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