Insights into the DNA damage response and tumor drug resistance

DDR-related mechanisms of chemoresistance to DNA-damaging agents. Resistance to DNA-damaging agents can result from recovery of DDR activity after genetic mutation of DDR genes, PTM alterations in DDR proteins, and epigenetic remodeling. ① Genetic reversion of DDR deficiency. Treatment with DNA-damaging agents can cause secondary mutations leading to partial or complete restoration of DDR protein activity, as shown for BRCA2. ② Allelic variation in DDR genes has differential effects on the chemotherapy response. C124R and C129E are 2 common missense mutations in PTEN that decrease PTEN stability or confer gain of function, respectively. ③ Pathway rewiring caused by genetic mutation of DDR genes shifts the balance among DDR pathways, such as 53BP1-mediated NHEJ and BRCA1-mediated HR. ④ PTMs modulate DDR signal transduction, as shown for ATM/CHK2-catalyzed phosphorylation after DSB induction. ⑤ PTMs regulate DDR protein stability. C1QBP stabilizes MRE11/RAD50 and protects it from degradation, and inhibits MRE11-dependent nonspecific resection in the absence of stress conditions. In the case of DSBs, ATM phosphorylates MRE11; subsequently, C1QBP dissociation from MRE11/RAD50 promotes MRE11/RAD50/NBS1 (MRN) complex assembly and DSB end resection. ⑥ PTMs control the phase separation of DDR factors. LLPS of FUS is inhibited by its methylation and phosphorylation. ⑦ Chromatin relaxation surrounding DNA damage sites is responsible for efficient DDR protein accumulation and the promotion of chemoresistance. After DSB formation, histone PARylation triggers nucleosomal disassembly, and chromatin remodelers such as ALC1, CHD4, and MORC2 orchestrate further alterations in chromatin structure. ⑧ Histone PTMs affect DDR factor accumulation and DDR pathway choice. For example, H2AK15 monoubiquitination and H4K20 dimethylation promote 53BP1-mediated NHEJ and antagonize BRCA1-mediated HR at DSBs. ⑨ DNA epigenetic modifications modulate DDR protein expression, as shown for the promoter methylation or acetylation of BRCA1. 53BP1, p53 binding protein 1; ALC1, amplified in liver cancer 1; ATM, ataxia telangiectasia mutated; BARD1, BRCA1 associated RING domain 1; BRCA1, breast cancer type 1 susceptibility protein; BRCA2, breast cancer type 2 susceptibility protein; C1QBP, complement C1q binding protein; CHD4, chromodomain helicase DNA binding protein 4; CHK2, checkpoint kinase 2; DSB, double-strand break; FUS, fused in sarcoma; H2AK15, histone H2A lysine 15; H4K20, histone 4 lysine 20; HR, homologous recombination; KAP1, KRAB-associated protein 1; MORC2, microrchidia CW-type zinc finger 2; MRE11, meiotic recombination 11; NBS1, Nijmengen breakage syndrome 1; NHEJ, non-homologous end-joining; PARP1/2, poly(ADP-ribose) polymerase 1/2; PTEN, phosphatase and tensin homolog; RIF1, replication timing regulatory factor 1. Figure was created in Word Processing System (WPS) and Figdraw.