Non-homologous end-joining

Yeast H2A has the PI-3 kinase motif found in mammalian H2AX. This motif is important for yeast to repair DSBs and in non-homologous end joining. The yeast enzyme catalyzing phosphorylation of yeast H2AX at Ser-129 (homologous to serine 139 of mammalian H2AX) is Mecl [100] (Fig. 8). 

Neema M, Navarro-Quiroga I, Chechlacz M, Gilliams-Francis K, Liu J, et al. 2005. DNA damage and non-homologous end joining in excitotoxicity Neuroprotective role of DNA-pkcs in kainic acid-induced seizures. Hippocampus 15 1057-1071. 

Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, Yamaguchi-Iwai Y, Shinohara A, Takeda S. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 1998 17 5497-5508. 

Reddy YV, Ding Q, Lees-Miller SP, Meek K, Ramsden DA. Non homologous end joining requires that the DNA-PK complex undergo an autophosphorylation-dependent rearrangement at DNA ends. J. Biol. Chem. 2004 279 39408-39413. 

There are six general mechanisms of DNA repair direct repair (DR), nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination repair (HRR), and non-homologous end joining (NHEJ). 

Figure 2 DNA damage induced by ionizing radiation. A) DNA damage and repair. All the constitutive elements of DNA (sugar-phosphate backbone and bases) are possibly modified by ionizing radiation. Single strand breaks (SSB), oxidized bases and abasic site are processed by base excision repair (BER), double strand breaks (DSB) by homologous recombination and non homologous end joining (HR and NHEJ) and DNA-protein crosslinks by nucleotide excision repair (NER). B) Quantitative measurement of radiation-induced and spontaneous DNA damage.

Double strand breaks repair by homologous recombination and non-homologous end joining... 

When strand breaks remain open at a lesion site, or when non-repaired damage blocks the progress of a DNA rephcation fork to produce a daughter strand gap, a complex cascade of reactions is triggered to stop the cell cycle machinery and recruit repair factors. When, after replication, a second identical DNA copy is available, homologous recombination (HR) seems to be preferred otherwise cells rely on non-homologous end joining (NHEJ), which is more error-prone [17]. 

Rassool FV (2003) DNA double strand breaks (DSB) and non-homologous end joining (NHEJ) pathways in human leukemia. Cancer Lett 193 1-9... 

Ma, Y, Pannicke, U., Schwarz, K., and Lieber, M. (2002). Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in non-homologous end joining and V(D)J recombination. Cell 108, 781-794. 

Double strand break reipair. There are two main pathways for DSBR, error-prone non-homologous end-joining (NHEJ) and error-free homologous recombination (HR). NHEJ seems to be the predominant pathway in mammalian cells, however cell cycle phase also plays a role in the choice of pathway. NHEJ occurs in GO/Gl, whereas HR occurs in late S... 

Two major pathways, HR and non-homologous end-joining (NHEJ), have evolved to deal with DSBs, and are conserved from yeast to vertebrates. Despite the conservation of these pathways, their relative contribution to DSB repair varies greatly between these two species. HR plays a dominant role in any DSB repair in yeast, whereas NHEJ significantly contributes to DSB repair in vertebrates. Much more details on this issue are provided in chapter 14. NHEJ is a pathway that rejoins DNA ends, usually after removal of a Hmited number of base pairs. It is initiated by the Ku70/Ku80 heterodimer, which binds to DNA ends and recruits the DNA-PKcs- The latter can phosphorylate a variety of repair proteins. 

Sartori AA, Lukas C, Coates J et al (2007) Human CtIP promotes DNA end resection. Nature 450 509-514 Schulte-Uentrop L, El-Awady RA, Schliecker L et al (2008) Distinct roles of XRCC4 and Ku80 in non-homologous end-joining of endonuclease- and ionizing radiation-induced DNA double-strand breaks. Nucleic Acids Res 36 2561-2569... 

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