Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function

Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function Mutations affecting the C-terminal WD40 domain of PALB2 (amino acids 853-1186) impair its ability to interact with BRCA2, RAD51 and/or RAD51C (Erkko et al. 2007, Park et al. 2014). In addition, disruption of the WD40 domain can lead to the exposure of the nuclear export signal (NES) and cytoplasmic translocation of PALB2 (Pauty et al. 2017). Mutations affecting the C-terminal domain of PALB2 are more frequent than mutations that affect the N-terminus and have been observed, as germline mutations, in familial breast cancer and in Fanconi anemia, but somatic mutations also occur in sporadic cancers. Cells that express PALB2 mutants defective in BRCA2, RAD51 and/or RAD51C binding show reduced ability to perform DSBR via homologous recombination repair, form fewer RAD51 foci at DSBR sites, and are sensitive to DNA crosslinking agents such as mitomycin C (Erkko et al. 2007, Park et al. 2014).