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

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R-HSA-9701193
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Homo sapiens
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Biallelic loss-of-function mutations in PALB2 results in Fanconi anemia subtype N (FA-N), which is phenotypically very similar to Fanconi anemia subtype D1, caused by biallelic loss-of-function of BRCA2 (Reid et al. 2007). FA-D1 and FA-N are characterized by developmental abnormalities, bone marrow failure and childhood cancer susceptibility, especially childhood solid tumors, such as Wilms tumor and medulloblastoma. Monoallelic PALB2 loss-of-function is an underlying cause of hereditary breast cancer in particular, but inactivating PALB2 mutations are also to a lesser extent found in some other cancer types, including pancreatic cancer (Erkko et al. 2007, Erkko et al. 2008, Antoniou et al. 2014, Yang et al. 2020). Germline PALB2 mutations are somewhat less frequent than those occurring in BRCA1 and BRCA2, but cause a comparably high risk of developing breast cancer. Therefore, PALB2 is a high-risk breast cancer predisposing gene (Nepomuceno et al. 2021).

PALB2 interacts with both BRCA1 and BRCA2, and serves as a bridge that connects BRCA2 with BRCA1 at sites of DNA double-strand break repair (DSBR). PALB2 also interacts directly with DNA and takes part in the regulation of RAD51-mediated homologous recombination (Buisson et al. 2010; Dray et al. 2010). PALB2 loss-of-function mutations can affect its interaction with BRCA1 when they affect the N-terminal coiled-coil domain that is necessary for BRCA1 binding (Sy et al. 2009, Foo 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 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), with some variants also presenting sensitivity to PARP inhibitors (Foo et al. 2017).

Mutations evaluated so far in the central region of PALB2, which contains the ChAM motif and the MRG15-binding region, have shown no functional impact on the protein.

Mutations affecting the C-terminal WD40 domain of PALB2 impair its ability to interact with BRCA2, RAD51 and/or RAD51C (Erkko et al. 2007, Park et al. 2014, Simhadri et al. 2019). In addition, disruption of the WD40 domain can lead to the exposure of a nuclear export signal (NES), leading to 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, Parker et al. 2014).

For review, please refer to Tischkowitz and Xia 2010, Pauty et al. 2014, Park et al. 2014, Nepomuceno et al. 2017, Ducy et al. 2019, Wu et al. 2020, Nepomuceno et al. 2021.

Literature References
PubMed ID Title Journal Year
18628482 Penetrance analysis of the PALB2 c.1592delT founder mutation

Erkko, H, Dowty, JG, Nikkilä, J, Syrjäkoski, K, Mannermaa, A, Pylkäs, K, Southey, MC, Holli, K, Kallioniemi, A, Jukkola-Vuorinen, A, Kataja, V, Kosma, VM, Xia, B, Livingston, DM, Winqvist, R, Hopper, JL

Clin Cancer Res 2008
20871616 Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2

Dray, E, Etchin, J, Wiese, C, Saro, D, Williams, GJ, Hammel, M, Yu, X, Galkin, VE, Liu, D, Tsai, MS, Sy, SM, Schild, D, Egelman, E, Chen, J, Sung, P

Nat. Struct. Mol. Biol. 2010
17200671 Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer

Reid, S, Schindler, D, Hanenberg, H, Barker, K, Hanks, S, Kalb, R, Neveling, K, Kelly, P, Seal, S, Freund, M, Wurm, M, Batish, SD, Lach, FP, Yetgin, S, Neitzel, H, Ariffin, H, Tischkowitz, M, Mathew, CG, Auerbach, AD, Rahman, N

Nat Genet 2007
32185139 Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Wu, S, Zhou, J, Zhang, K, Chen, H, Luo, M, Lu, Y, Sun, Y, Chen, Y

Front Oncol 2020
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
24998779 PALB2: the hub of a network of tumor suppressors involved in DNA damage responses

Park, JY, Zhang, F, Andreassen, PR

Biochim Biophys Acta 2014
20858716 PALB2/FANCN: recombining cancer and Fanconi anemia

Tischkowitz, M, Xia, B

Cancer Res 2010
30337689 PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response

Simhadri, S, Vincelli, G, Huo, Y, Misenko, S, Foo, TK, Ahlskog, J, Sørensen, CS, Oakley, GG, Ganesan, S, Bunting, SF, Xia, B

Oncogene 2019
25337756 Breast-cancer risk in families with mutations in PALB2

Antoniou, AC, Foulkes, WD, Tischkowitz, M

N Engl J Med 2014
20871615 Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination

Buisson, R, Dion-Côté, AM, Coulombe, Y, Launay, H, Cai, H, Stasiak, AZ, Stasiak, A, Xia, B, Masson, JY

Nat. Struct. Mol. Biol. 2010
24870022 Exploring the roles of PALB2 at the crossroads of DNA repair and cancer

Pauty, J, Rodrigue, A, Couturier, A, Buisson, R, Masson, JY

Biochem J 2014
30638972 The Tumor Suppressor PALB2: Inside Out

Ducy, M, Sesma-Sanz, L, Guitton-Sert, L, Lashgari, A, Gao, Y, Brahiti, N, Rodrigue, A, Margaillan, G, Caron, MC, Côté, J, Simard, J, Masson, JY

Trends Biochem Sci 2019
31841383 Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Yang, X, Leslie, G, Doroszuk, A, Schneider, S, Allen, J, Decker, B, Dunning, AM, Redman, J, Scarth, J, Plaskocinska, I, Luccarini, C, Shah, M, Pooley, K, Dorling, L, Lee, A, Adank, MA, Adlard, J, Aittomäki, K, Andrulis, IL, Ang, P, Barwell, J, Bernstein, JL, Bobolis, K, Borg, Å, Blomqvist, C, Claes, KBM, Concannon, P, Cuggia, A, Culver, JO, Damiola, F, de Pauw, A, Díez, O, Dolinsky, JS, Domchek, SM, Engel, C, Evans, DG, Fostira, F, Garber, J, Golmard, L, Goode, EL, Gruber, SB, Hahnen, E, Hake, C, Heikkinen, T, Hurley, JE, Janavicius, R, Kleibl, Z, Kleiblova, P, Konstantopoulou, I, Kvist, A, Laduca, H, Lee, ASG, Lesueur, F, Maher, ER, Mannermaa, A, Manoukian, S, McFarland, R, McKinnon, W, Meindl, A, Metcalfe, K, Mohd Taib, NA, Moilanen, J, Nathanson, KL, Neuhausen, S, Ng, PS, Nguyen-Dumont, T, Nielsen, SM, Obermair, F, Offit, K, Olopade, OI, Ottini, L, Penkert, J, Pylkäs, K, Radice, P, Ramus, SJ, Rudaitis, V, Side, L, Silva-Smith, R, Silvestri, V, Skytte, AB, Slavin, T, Soukupova, J, Tondini, C, Trainer, AH, Unzeitig, G, Usha, L, van Overeem Hansen, T, Whitworth, J, Wood, M, Yip, CH, Yoon, SY, Yussuf, A, Zogopoulos, G, Goldgar, D, Hopper, JL, Chenevix-Trench, G, Pharoah, P, George, SHL, Balmaña, J, Houdayer, C, James, P, El-Haffaf, Z, Ehrencrona, H, Janatova, M, Peterlongo, P, Nevanlinna, H, Schmutzler, R, Teo, SH, Robson, M, Pal, T, Couch, F, Weitzel, JN, Elliott, A, Southey, M, Winqvist, R, Easton, DF, Foulkes, WD, Antoniou, AC, Tischkowitz, M

J Clin Oncol 2020
24141787 Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair

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

Oncogene 2014
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

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

Nucleic Acids Res 2017
28319063 Compromised BRCA1-PALB2 interaction is associated with breast cancer risk

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

Oncogene 2017
22941656 PALB2 self-interaction controls homologous recombination

Buisson, R, Masson, JY

Nucleic Acids Res 2012
28858227 The Role of PALB2 in the DNA Damage Response and Cancer Predisposition

Nepomuceno, TC, De Gregoriis, G, de Oliveira, FMB, Suarez-Kurtz, G, Monteiro, AN, Carvalho, MA

Int J Mol Sci 2017
17287723 A recurrent mutation in PALB2 in Finnish cancer families

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

Nature 2007
33139182 PALB2 Variants: Protein Domains and Cancer Susceptibility

Nepomuceno, TC, Carvalho, MA, Rodrigue, A, Simard, J, Masson, JY, Monteiro, ANA

Trends Cancer 2021
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cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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