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Fig. 3 | Molecular Cancer

Fig. 3

From: PARP inhibitor resistance: the underlying mechanisms and clinical implications

Fig. 3

Schematic describing the function of PARP1 and BRCA1/2 in protection of DNA replication fork and mechanisms of protection of DNA replication fork leading to PARPi resistance. a PARPi trap PARP1 on DNA and cause fork stalling. After fork stalling, PRA is phosphorylated and ssDNA is coated by PRA rapidly. Then, RAD51 replaces RPA and mediates replication fork reversal. The revered fork can be degraded by MRE11 and MUS81. BRCA1/2 is relied on to protect nascent DNA replication forks from degradation. EZH2 induces H3K27 methylation and MUS81 recruitment at stalled forks. MELL3/4 induces H3K4 methylation increases the accumulation of PTIP, which leads to the recruitment of MRE11. FANCD2 suppresses MRE11-mediated fork degradation, which can be reversed by SMARCAL1. RADX blocks the recruitment of RAD51 at replication forks. b In BRCA1/2-deficient cells, low expression of PARP1, RADX, SMARCAL1, EZH2, PTIP, MELL3/4 and high expression of FANCD2 confer resistance of PARPi

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