Five DNA repair pathways. (A) DSBs are repaired by 2 NHEJ and 2 HR subpathways. Classic NHEJ initiates with broken ends bound by Ku, which protects ends, leading to accurate or semi-accurate repair. Mutations in classic NHEJ factors shunt DSBs toward alternative NHEJ, which involves limited resection by MRN/CtIP and annealing via microhomology, yielding inaccurate repair. 53BP1 also serves to increase NHEJ accuracy by blocking MRN/CtIP resection. PARP1 promotes more extensive end-resection by EXO1 and BLM to reveal ssDNA and promote HR. RPA binds to ssDNA, BRCA2 mediates replacement of RPA with RAD51, the RAD51 nucleoprotein filament invades a homologous donor sequence (typically the sister chromatid in S/G₂ phase), and repair synthesis extends the invading 3′ end, which then anneals with resected end to provide accurate repair. If long homologous repeats flank the DSB (white boxes), extensive resection can reveal complementary ssDNA that is annealed in a reaction promoted by RAD52, leading to deletion of one repeat and DNA between repeats, or translocations if DSBs occur on different chromosomes. (B) Base damage, often from oxidation, triggers base excision repair (BER). This results in a short repaired single-strand segment, also called a patch. Bulky nucleotide lesions, such as thymidine dimmers from ultraviolet light, are repaired by nucleotide excision repair (NER). These involve a long repaired single-strand patch. Mismatch repair (MMR), used to replace nucleotides mistakenly placed opposite a nonpaired template nucleotide during DNA synthesis, involves long excision of single strands and resynthesis repair patches initiated from existing or induced nicks.