Relationships between DNA repair pathways. (A) DNA repair and DNA damage tolerance pathways are highly networked. Each double-headed arrow indicates a known functional interaction between pathways and/or cases where one or more proteins function in 2 pathways. For example, mismatches arise in strand exchange intermediates during HR and are acted on by the mismatch repair machinery, and interstrand crosslink repair involves proteins from several pathways, including NER, HR, and translesion DNA synthesis. Also, most DNA repair occurs in chromatin, and all repair and signaling pathways are also regulated by chromatin modification pathways. (B) Understanding DNA repair networks can lead to new cancer therapies based on synthetic lethal interactions, but these networks also are a mechanism by which the cancer cell can escape synthetic lethality. In this diagram, a hypothetical DNA repair and signaling network is illustrated. DNA damage can be processed by DNA repair pathways (denoted R1, R2, R3) or is bypassed during replication by damage tolerance pathways (T1, T2). DNA damage also activates multiple arrest signaling pathways for activation of repair and inhibition of cell-cycle progression, indicated by S1 and S2. Each repair or tolerance pathway leads to either repair or bypass of lesions and promotes survival. Signaling pathways may activate (arrows) or inhibit (blocked lines) specific DNA repair or mutation tolerance pathways. These pathways ultimately regulate cell-cycle progression. Blocking any of these pathways, not just repair (via mutation at the origination of the cancer, or with chemotherapy), provides numerous opportunities to exploit synthetic lethal interactions. However, highly interconnected networks also present challenges, because blocking 2 pathways may simply shunt damage to a third pathway. It is also possible that synthetic lethality may be suppressed through accumulation of additional mutations, that is, by activating positive regulatory pathways, or by inactivating negative regulatory pathways. Thus, one worry with this approach is that cancer cells will ultimately become resistant to these synthetic lethal drugs by adapting alternative repair or lesion bypass pathways.