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

Stable Identifier
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
28158555 Cancer-causing mutations in the tumor suppressor PALB2 reveal a novel cancer mechanism using a hidden nuclear export signal in the WD40 repeat motif

Caron, MC, Masson, JY, Coulombe, Y, Rodrigue, A, Couturier, AM, Pauty, J, Dellaire, G

Nucleic Acids Res 2017
17287723 A recurrent mutation in PALB2 in Finnish cancer families

Livingston, DM, Syrjäkoski, K, Pylkäs, K, Kosma, VM, Xia, B, Karppinen, SM, Miron, A, Kataja, V, Bell, DW, Mannermaa, A, Drapkin, RI, Li, G, Grip, M, Winqvist, R, Schleutker, J, Soini, Y, Rapakko, K, Mustonen, A, Nikkilä, J, Reiman, M, Sheng, Q, Erkko, H, Mattila, H, Jukkola-Vuorinen, A, Aaltonen, LA, Kere, J, Kallioniemi, A, Haber, DA

Nature 2007
24141787 Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair

Park, JY, Nassar, N, Freund, M, Andreassen, PR, Hanenberg, H, Meetei, AR, Singh, TR, Zhang, F

Oncogene 2014
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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