Homology directed repair (HDR) of DNA double strand breaks (DSBs) requires resection of DNA DSB ends. Resection creates 3'-ssDNA overhangs which then anneal with a homologous DNA sequence. This homologous sequence can then be used as a template for DNA repair synthesis that bridges the DSB. HDR preferably occurs through the error-free homologous recombination repair (HRR), but can also occur through the error-prone single strand annealing (SSA), or the least accurate microhomology-mediated end joining (MMEJ).
HRR and SSA share the initial steps that involve ATM signaling, formation of the so-called ionizing radiation-induced foci (IRIF), extensive resection of DNA DSB ends and activation of ATR signaling. In homologous recombination, 3'-ssDNA overhangs anneal with complementary sister chromatid strands. In SSA, 3'-ssDNA overhangs anneal with each other through homologous direct repeats contained in each overhang, resulting in deletions of one of the repeats and the DNA sequence in between the repeats during DNA repair synthesis.
Contrary to HRR and SSA, which both involve annealing of long stretches of highly homologous DNA sequences, MMEJ entails annealing of short regions of two 3'-ssDNA overhangs (up to 20 nucleotides) and is therefore more promiscuous and more likely to join unrelated DNA molecules. The error rate of MMEJ is additionally increased by the low fidelity of the DNA polymerase theta (POLQ), which performs DNA repair synthesis in MMEJ.
For reviews of this topic, please refer to Khanna 2001, Thompson and Schild 2001, Thompson and Schild 2002, Thompson and Limoli 2003, Ciccia and Elledge 2010.
