Microhomology-mediated end joining

Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee,[1] the foremost distinguishing property of MMEJ is the use of 5–25 base pair (bp) microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. Thus, MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements.

Two other well-known means of double-strand breakage repair are non-homologous end joining and homologous recombination. MMEJ is distinguished from the other repair mechanisms by its use of 5–25 base pair microhomologous sequences to align the broken strands before joining. MMEJ uses a Ku protein and DNA-PK independent repair mechanism, and repair occurs during the S-phase of the cell cycle, as opposed to the G0/G1 and early S-phases in NHEJ and late S to G2-phase in HR.

MMEJ works by ligating the mismatched hanging strands of DNA, removing overhanging nucleotides, and filling in the missing base pairs. When a break occurs, a homology of 5 - 25 complementary base pairs on both strands is identified and used as a basis for which to align the strands with mismatched ends. Once aligned, any overhanging bases (flaps) and mismatched bases on the strands are removed and any missing nucleotides are inserted. As this method's only way of identifying if the two strands are related is based on microhomology down/upstream from the site of breakage, it does not identify any missing base pairs which may have been lost during the break, and even removes nucleotides (flaps) in order to ligate the strand. MMEJ ligates the DNA strands without checking for consistency and causes deletions, since it removes base pairs (flaps) in order to align the two pieces.

MMEJ is an error-prone method of repair and results in deletion mutations in the genetic code, which may initiate the creation of oncogenes that could lead to the development of cancer. In most cases a cell uses MMEJ only when the NHEJ method is unavailable or unsuitable, due to the disadvantage posed by introducing deletions into the genetic code.

Genes required for MMEJ

A biochemical assay system shows that at least 6 genes are required for microhomology-mediated end joining: FEN1, Ligase III, MRE11, NBS1, PARP1 and XRCC1.[2] All six of these genes are up-regulated in one or more cancers.

MMEJ in cancer

FEN1 is over-expressed in the majority of cancers of the breast,[3] prostate,[4] stomach,[5][6] neuroblastomas,[7] pancreatic,[8] and lung.[9]

Ligase III is upregulated in chronic myeloid leukemia,[10] multiple myeloma,[11] and breast cancer.[12]

MRE11 is over-expressed in breast cancers.[13]

NBS1 is over-expressed in some prostate cancers,[14] in head and neck cancer,[15] and in squamous cell carcinoma of the oral cavity.[16]

PARP1 is over-expressed in tyrosine kinase-activated leukemias,[17] in neuroblastoma,[18] in testicular and other germ cell tumors,[19] and in Ewing’s sarcoma,[20]

XRCC1 is over-expressed in non-small-cell lung carcinoma (NSCLC),[21] and at an even higher level in metastatic lymph nodes of NSCLC.[22] Perhaps even more interesting, deficiency in XRCC1, due to being heterozygous for a mutated XRCC1 gene coding for a truncated XRCC1 protein, suppresses tumor growth in mice in three experimental conditions for inducing three types of cancer (colon cancer, melanoma or breast cancer).[23]

MMEJ always involves at least a small deletion, so that it is a mutagenic pathway.[24] Several other pathways can also repair double-strand breaks in DNA, including the less inaccurate pathway of non-homologous end joining (NHEJ) and accurate pathways using homologous recombinational repair (HRR).[25] Various factors determine which pathway will be used for repair of double strand breaks in DNA.[24] When FEN1, Ligase III, MRE11, NBS1, PARP1 or XRCC1 are over-expressed (this occurs with FEN1 when its promoter is hypomethylated[3]) the highly inaccurate MMEJ pathway may be favored, causing a higher rate of mutation and increased risk of cancer.

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[26] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[26] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, FEN1, Ligase III, MRE1, PARP1, NBS1 and XRCC1 mediated MMEJ repair is highly inaccurate, so in these cases, over-expression, rather than under-expression, leads to cancer. This is supported by the observation that reduction of mutagenic XRCC1 mediated MMEJ repair leads to reduced progression of cancer.[23]

References

  1. ↑ McVey M, Lee SE (2008). "MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings". Trends Genet. 24 (11): 529–38. doi:10.1016/j.tig.2008.08.007. PMID 18809224.
  2. ↑ Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis. 6: e1697. doi:10.1038/cddis.2015.58. PMC 4385936Freely accessible. PMID 25789972.
  3. 1 2 Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B (2008). "Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers". Mol. Cancer Res. 6 (11): 1710–7. doi:10.1158/1541-7786.MCR-08-0269. PMC 2948671Freely accessible. PMID 19010819.
  4. ↑ Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS (2006). "Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score". BJU Int. 98 (2): 445–51. 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 (2005). "Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells". Clin. Cancer Res. 11 (2 Pt 1): 473–82. PMID 15701830.
  6. ↑ Wang K, Xie C, Chen D (2014). "Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis". Int. J. Mol. Med. 33 (5): 1268–74. 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 (2005). "Genome-wide analysis of gene expression in neuroblastomas detected by mass screening". Cancer Lett. 225 (1): 111–20. doi:10.1016/j.canlet.2004.10.035. 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 (2003). "Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays". Am. J. Pathol. 162 (4): 1151–62. doi:10.1016/S0002-9440(10)63911-9. PMC 1851213Freely accessible. PMID 12651607.
  9. ↑ Nikolova T, Christmann M, Kaina B (2009). "FEN1 is overexpressed in testis, lung and brain tumors". Anticancer Res. 29 (7): 2453–9. PMID 19596913.
  10. ↑ Sallmyr A, Tomkinson AE, Rassool FV (2008). "Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks". Blood. 112 (4): 1413–23. doi:10.1182/blood-2007-07-104257. PMC 2967309Freely accessible. PMID 18524993.
  11. ↑ Herrero AB, San Miguel J, Gutierrez NC (2015). "Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability". PLoS ONE. 10 (3): e0121581. doi:10.1371/journal.pone.0121581. PMC 4366222Freely accessible. PMID 25790254.
  12. ↑ Tobin LA, Robert C, Nagaria P, Chumsri S, Twaddell W, Ioffe OB, Greco GE, Brodie AH, Tomkinson AE, Rassool FV (2012). "Targeting abnormal DNA repair in therapy-resistant breast cancers". Mol. Cancer Res. 10 (1): 96–107. doi:10.1158/1541-7786.MCR-11-0255. PMC 3319138Freely accessible. PMID 22112941.
  13. ↑ Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, Lo S (2012). "Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer". J. Natl. Cancer Inst. 104 (19): 1485–502. 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 (2014). "NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer". Oncotarget. 5 (22): 11081–90. doi:10.18632/oncotarget.2404. PMC 4294365Freely accessible. PMID 25415046.
  15. ↑ Yang MH, Chiang WC, Chou TY, Chang SY, Chen PM, Teng SC, Wu KJ (2006). "Increased NBS1 expression is a marker of aggressive head and neck cancer and overexpression of NBS1 contributes to transformation". Clin. Cancer Res. 12 (2): 507–15. 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 (2010). "Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity". Cancer Sci. 101 (4): 1029–37. 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 (2015). "c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias". Mol. Cancer Res. 13 (4): 699–712. doi:10.1158/1541-7786.MCR-14-0422. PMC 4398615Freely accessible. PMID 25828893.
  18. ↑ Newman EA, Lu F, Bashllari D, Wang L, Opipari AW, Castle VP (2015). "Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma". Mol. Cancer Res. 13 (3): 470–82. 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 (2013). "PARP expression in germ cell tumours". J. Clin. Pathol. 66 (7): 607–12. doi:10.1136/jclinpath-2012-201088. PMID 23486608.
  20. ↑ Newman RE, Soldatenkov VA, Dritschilo A, Notario V (2002). "Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells". Oncol. Rep. 9 (3): 529–32. 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 (2010). "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". Lung Cancer. 68 (3): 478–83. 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 (2009). "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". J Thorac Oncol. 4 (11): 1307–12. doi:10.1097/JTO.0b013e3181b9f236. PMID 19745766.
  23. 1 2 Pettan-Brewer C, Morton J, Cullen S, Enns L, Kehrli KR, Sidorova J, Goh J, Coil R, Ladiges WC (2012). "Tumor growth is suppressed in mice expressing a truncated XRCC1 protein". Am J Cancer Res. 2 (2): 168–77. PMC 3304571Freely accessible. PMID 22432057.
  24. 1 2 Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA (2005). "Modulation of DNA end joining by nuclear proteins". J. Biol. Chem. 280 (36): 31442–9. doi:10.1074/jbc.M503776200. PMID 16012167.
  25. ↑ Ottaviani D, LeCain M, Sheer D (2014). "The role of microhomology in genomic structural variation". Trends Genet. 30 (3): 85–94. doi:10.1016/j.tig.2014.01.001. PMID 24503142.
  26. 1 2 Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer

General references

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