Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function

Stable Identifier
R-HSA-9704331
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Pathway
Species
Homo sapiens
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Mutations in the N-terminal coiled-coil domain of PALB2 (amino acids 9-44), involved in self-interaction and BRCA1 binding, impair the interaction of PALB2 with BRCA1 (Sy et al. 2009, Foo et al. 2017, Boonen et al. 2020). Phosphorylation of PALB2 by ATR on serine residue S59 promotes BRCA1-PALB2 interaction and the localization of PALB2 to DNA damage sites (Buisson et al. 2017). Mutations in the coiled-coil domain can also affect PALB2 self-interaction, recruitment to double-strand break sites, homologous recombination repair, and RAD51 foci formation (Buisson and Masson 2012). PALB2 missense mutants that do not bind to BRCA1 can still be recruited to DNA double-strand break repair (DSBR) sites, probably through interaction with other proteins involved in DSBR, but they are unable to restore efficient gene conversion in PALB2-deficient cells and they render cells hypersensitive to the DNA damaging agent mitomycin C (Sy et al. 2009). Some variants in this region are also sensitive to PARP inhibitors (Foo et al. 2017).

Literature References
PubMed ID Title Journal Year
19369211 PALB2 is an integral component of the BRCA complex required for homologous recombination repair

Sy, SM, Huen, MS, Chen, J

Proc Natl Acad Sci U S A 2009
28319063 Compromised BRCA1-PALB2 interaction is associated with breast cancer risk

Burke, KA, Foo, TK, Boshari, T, Xia, B, Riaz, N, Neuhausen, SL, Reis-Filho, JS, Foulkes, WD, Tischkowitz, M, Blecua, P, Zayed, N, Ding, YC, Weigelt, B, Simhadri, S, Berman, SH, Huo, Y

Oncogene 2017
22941656 PALB2 self-interaction controls homologous recombination

Masson, JY, Buisson, R

Nucleic Acids Res 2012
33195396 Functional Characterization of PALB2 Variants of Uncertain Significance: Toward Cancer Risk and Therapy Response Prediction

Vreeswijk, MPG, Boonen, RACM, van Attikum, H

Front Mol Biosci 2020
28089683 Coupling of Homologous Recombination and the Checkpoint by ATR

Haas, W, Zou, L, Xia, B, Foo, TK, Masson, JY, Rodrigue, A, Niraj, J, Kreuzer, J, Buisson, R, Dellaire, G, Hardy, EJ, Ho, CK

Mol Cell 2017
Participants
Participates
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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