Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function of PALB2 in binding to BRCA2/RAD51/RAD51C

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R-HSA-9704408
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Reaction [FailedReaction]
Species
Homo sapiens
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The WD40 domain located in the C-terminus of PALB2, between amino acid residues 853-1186, enables binding of PALB2 to BRCA2, RAD51, RAD51C, RNF168 and POLN (Luijsterburg et al. 2017, Buisson 2014). The synthetic truncation mutant of PALB2, PALB2deltaC, which ends at the proline residue P1097, lacks blades 5-7 of the WD40 domain and is completely unable to interact with RAD51C, RAD51 and BRCA2 (Park et al. 2014). Truncating nonsense and frameshift mutations in PALB2 that entirely or partially perturb the WD40 domain, as well as missense mutations in the WD40 domain are found in cancer (including familial breast cancer) and Fanconi anemia patients and are associated with impaired PALB2 binding to BRCA2, RAD51 and/or RAD51C, impaired assembly of RAD51 DNA double-strand break (DSB) repair foci, defective homologous recombination repair (HRR), and cellular sensitivity to DNA crosslinking agents such as mitomycin C (Erkko et al. 2007, Tischkowitz et al. 2007, Xia et al. 2007, Zhang et al. 2007, Park et al. 2014, Foo et al. 2017, Rodrigue et al. 2019, Boonen et al. 2019, Wiltshire et al. 2020). The WD40 domain is also important for PALB2 stability, as the PALB2 Y1183* mutant, which lacks the last four amino acids of PALB2, does not fold completely and is thus susceptible to degradation (Reid et al. 2007, Oliver et al. 2009). Many of the characterized missense mutations in the WD40 domain are associated with reduced PALB2 protein levels, thought to be due to reduced protein stability (Boonen et al. 2019, reviewed in Boonen et al. 2020). In addition, this domain also contains, buried within the propeller structure, a nuclear export signal (NES). Some of the WD40 missense mutants of PALB2 show moderate to significant cytosolic accumulation, possibly due to unmasking of the C terminal nuclear export signal (Rodrigue et al. 2019). The cancer mutant PALB2 W1038* is mislocalized to the cytoplasm, which impacts the functionality of PALB2 (Pauty et al. 2017). The following missense mutants described below also show mislocalization to the cytoplasm: PALB2 I944N, PALB2 L1070P, PALB2 L947F, PALB2 L947S, PALB2 T1030I, PALB2 G1043A, PALB2 L1119P and PALB2 W1140G (Wiltshire et al. 2019, Rodrigue et al. 2019).

The following PALB2 missense mutations that affect the WD40 domain have been shown to be defective in binding to BRCA2, RAD51 and/or RAD51C or to be defective in formation of RAD51 foci:
PALB2 W912G (Boonen et al. 2019: reduced number of RAD51 foci, defective HRR, sensitivity to PARP inhibitors, decreased protein stability)
PALB2 G937R (Boonen et al. 2019: modestly reduced number of RAD51 foci, defective HRR, sensitivity to PARP inhibitors, decreased protein stability)
PALB2 L939W (Park et al. 2014: significantly reduced binding to BRCA2 and RAD51, no significant effect on RAD51C binding, modest but significant decrease in DSB-initiated homologous recombination repair and assembly of RAD51 foci; Wiltshire et al. 2020: reduced binding to BRCA2 and RAD51)
PALB2 I944N (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors, decreased protein stability; Wiltshire et al. 2020: reduced binding to BRCA2 and RAD51, partially defective HRR)
PALB2 L947F (Rodrigue et al. 2019: significantly reduced binding to BRCA2, moderate cytosolic accumulation, significant decrease in the number of RAD51 foci; Wiltshire et al. 2020: partially defective HRR)
PALB2 L947S (Rodrigue et al. 2019: significantly reduced binding to BRCA2, moderate cytosolic accumulation, significant decrease in the number of RAD51 foci; Boonen et al. 2019: reduced protein stability, partially defective HRR, partial sensitivity to PARP inhibitors; modestly decreased number of RAD51 foci; Wiltshire et al. 2020: partially defective HRR)
PALB2 L961P (Boonen et al. 2019: reduced number of RAD51 foci, defective HRR, sensitivity to PARP inhibitors, sensitivity to cisplatin, decreased protein stability)
PALB2 T1030I (Park et al. 2014: no effect on BRCA2 binding, significant reduction in RAD51 and RAD51C binding, reduced protein stability; Rodrigue: significantly reduced binding to BRCA2, significant cytosolic accumulation, defective HRR, significant decrease in the number of RAD51 foci; Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors, decreased protein stability; Wiltshire et al. 2020: partially defective HRR)
PALB2 G1043A (Rodrigue et al. 2019: significantly reduced binding to BRCA2, partially defective HRR; Wiltshire et al. 2020: partially defective HRR)
PALB2 G1043D (Boonen et al. 2019: reduced number of RAD51 foci, defective HRR, sensitivity to PARP inhibitors, decreased protein stability)
PALB2 L1070P (Boonen et al. 2019: decreased protein stability; Wiltshire et al. 2020: reduced binding to BRCA2)
PALB2 L1119P (Rodrigue et al. 2019: significantly reduced binding to BRCA2, moderate cytosolic accumulation, partially defective HRR, persistent RAD51 foci – suggestive of defective disassembly of RAD51 foci; Boonen et al. 2019: no significant reduction in HRR efficiency, no significant sensitivity to PARP inhibitors; Wiltshire et al. 2020: partially defective HRR)
PALB2 W1140G (Rodrigue et al. 2019: significantly reduced binding to BRCA2, moderate cytosolic accumulation, partially defective HRR, significantly reduced number of RAD51 foci; Wiltshire et al. 2020: partially defective HRR)
PALB2 L1143P (Park et al. 2014: modest but significant reduction in binding to BRCA2, RAD51 and RAD51C, modest but significant decrease in DSB-initiated homologous recombination repair and assembly of RAD51 foci).

Although the synthetic missense variant PALB2 A1025R has normal expression level, it is impaired in homologous recombination (Boonen et al. 2019), confirming previous studies that showed an impaired interaction with BRCA2 (Oliver et al. 2009, Rodrigue et al. 2019, Wiltshire et al. 2020).

The following truncation (nonsense and frameshift) mutants on PALB2 were shown to be defective in binding to BRCA2, RAD51 and/or RAD51C:
PALB2 Y551* nonsense mutant, first identified in a Fanconi anemia patient, is unable to interact with BRCA2, RAD51C and largely with RAD51 (Xia et al. 2007, Park et al. 2014); it was also shown to be defective in HRR (Boonen et al. 2019, Wiltshire et al. 2020) and to confer sensitivity to PARP inhibitors (Boonen et al. 2019).
PALB2 L531Cfs*3 frameshift mutant (c.1592delT), frequently present in Finnish familial breast cancer cases, has little BRCA2 binding capacity and is defective in homologous recombination repair and crosslink repair (Erkko et al. 2007).
Two additional frameshift mutants of PALB2 associated with a strong family history of breast cancer and impaired in their ability to bind to BRCA2 are:
PALB2 C77Vfs100* (Tischkowitz et al. 2007)
PALB2 T841Qfs10* (Tischkowitz et al. 2007; this mutant was also reported in Fanconi anemia by Reid et al. 2007)

The following candidate WD40 domain missense mutants of PALB2 have been shown to be functionally impaired in HRR but their ability to bind to BRCA2, RAD51 or RAD51C, or to form RAD51 foci, has not been tested (as indicated), or they are predicted to be pathogenic and share sequence similarity with functionally studied PALB2 mutants:
PALB2 L972Q (Boonen et al. 2019: decreased protein stability, defective HRR, sensitivity to PARP inhibitors)
PALB2 I1037T (Boonen et al. 2019: decreased protein stability, defective HRR)
PALB2 G1043C (similar to PALB2 G1043A and PALB2 G1043D)
PALB2 L1172P (Boonen et al. 2019: decreased protein stability, defective HRR, sensitivity to PARP inhibitors)

Based on their similarity with the synthetic PALB2deltaC mutant, truncation mutants of PALB2 derived from COSMIC database (Forbes et al. 2017) which have not been functionally studied and whose amino acid sequence terminates before the terminal P1097 residue of PALB2deltaC, are annotated as candidate loss-of-function mutants for BRCA2, RAD51 and RAD51C binding. Several truncation mutants in PALB2 that have been reported in Fanconi anemia and/or hereditary breast cancer are also annotated as candidates (Reid et al. 2007, Rahman et al. 2007). In addition, several PALB2 truncation mutants that were shown to be functionally impaired in HRR, but whose ability to bind to BRCA2, RAD51 or RAD51C has not been tested are also annotated as candidates (reviewed in Boonen et al. 2020).

The following nonsense mutants of PALB2, reported in cancer, are annotated as candidates:
PALB2 Q66*
PALB2 Q228*
PALB2 E230* (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors)
PALB2 Q251* (Wiltshire et al. 2020: defective HRR)
PALB2 S254*
PALB2 E263*
PALB2 K346*
PALB2 Q370*
PALB2 E384*
PALB2 Y409* (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors)
PALB2 R414*
PALB2 L451*
PALB2 S518*
PALB2 E545*
PALB2 Q559*
PALB2 W575*
PALB2 Q613*
PALB2 E658*
PALB2 E667*
PALB2 R753* (also reporter in Fanconi anemia, Reid et al. 2007)
PALB2 G796*
PALB2 G808*
PALB2 Q822*
PALB2 L857*
PALB2 E860*
PALB2 E884*
PALB2 E943*
PALB2 E956*
PALB2 Q988* (reported in Fanconi anemia by Reid et al. 2007)
PALB2 E1002*
PALB2 W1038* (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors, reduced protein stability)
PALB2 Q1056*
PALB2 Q1091*
PALB2 Y1183* (this PALB2 mutant lacks only the four terminal amino acids, but was reported in hereditary breast cancer by Rahman et al. 2007 and in Fanconi anemia by Reid et al. 2007, the latter study suggesting that this is a null mutation, with no detectable protein; the mechanism is unclear, as significantly shorter C-terminally truncated PALB2 mutants are detectable)

The following frameshift mutants of PALB2, reported in cancer, are annotated as candidates:
PALB2 R37Cfs*5
PALB2 K43Rfs*10
PALB2 Q60Rfs*7 (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors, possibly a null variant)
PALB2 I76Mfs*4
PALB2 I76Yfs*101
PALB2 H130Tfs*47
PALB2 V132Afs*45 (reported in Fanconi anemia by Reid et al. 2007)
PALB2 S172Gfs*4 (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors, possibly a null variant)
PALB2 L176Nfs*3
PALB2 L253Yfs26* (reported in Fanconi anemia by Reid et al. 2007)
PALB2 I265Tfs*5
PALB2 N280Tfs*8
PALB2 I281Nfs*2
PALB2 M296*
PALB2 M296Nfs*7
PALB2 S299Yfs*3
PALB2 L304*
PALB2 F404Sfs*7
PALB2 I429Rfs*22
PALB2 H432Ffs*9
PALB2 F440Lfs*12
PALB2 N450Ifs*2
PALB2 P522Qfs*39
PALB2 F606Sfs*10
PALB2 P656Qfs*4
PALB2 E669Gfs*3 (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors)
PALB2 D715Efs*2 (Wiltshire et al. 2020: defective HRR)
PALB2 M723Vfs*21
PALB2 R794Sfs*57
PALB2 T799Pfs53* (reported in Fanconi anemia by Reid et al. 2008)
PALB2 F816Sfs*35
PALB2 W877Gfs*12
PALB2 C882Wfs*3 (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors)
PALB2 W898Efs*29
PALB2 A935*
PALB2 E956Kfs*6
PALB2 A995Cfs16* (reported in hereditary breast cancer by Rahman et al. 2007)
PALB2 L1006Ffs*5
PALB2 P1009Lfs*6 (Boonen et al. 2019: defective HRR, sensitivity to PARP inhibitors, reduced protein stability)
PALB2 E1010*
PALB2 I1035Mfs*6
PALB2 N1039Ifs2* (reported in Fanconi anemia by Reid et al. 2007 and in hereditary breast cancer by Rahman et al. 2007)
PALB2 K1098Nfs23* (reported in Fanconi anemia by Reid et al. 2007)
PALB2 Y1108Sfs*16 (Wiltshire et al. 2020: defective HRR)
PALB2 G1121Vfs*3 (Wiltshire et al. 2020: defective HRR)
PALB2 G1166Vfs*25 (Wiltshire et al. 2020: defective HRR)
A comprehensive list of variants in the PALB2 gene is provided at the Leiden Open Variation Database (LOVD) (https://databases.lovd.nl/shared/genes/PALB2) (Fokkema et al. 2011).

Literature References
PubMed ID Title Journal Year
17200671 Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer

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

Nat Genet 2007
24485656 Breast cancer proteins PALB2 and BRCA2 stimulate polymerase ? in recombination-associated DNA synthesis at blocked replication forks

Zhao, W, Masson, JY, Coulombe, Y, Pauty, J, Niraj, J, Maity, R, Buisson, R, Sung, P

Cell Rep 2014
17420451 Analysis of PALB2/FANCN-associated breast cancer families

Narod, SA, Sabbaghian, N, Omeroglu, A, Livingston, DM, Li, L, Xia, B, Lepage, P, Wong, N, van Beers, EH, Poll, A, Foulkes, WD, Tonin, PN, Khalil, T, Ashworth, A, Li, G, Reis-Filho, JS, Nederlof, PM, Tischkowitz, M, Quenneville, LA, Hamel, N

Proc Natl Acad Sci U S A 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
28240985 A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation

Boonen, RA, van den Heuvel, D, van Attikum, H, Caron, MC, Masson, JY, Mullenders, LH, Luijsterburg, MS, Couturier, AM, Wiegant, WW, Typas, D

Elife 2017
21520333 LOVD v.2.0: the next generation in gene variant databases

Laros, JF, Fokkema, IF, den Dunnen, JT, Celli, J, Taschner, PE, Schaafsma, GC

Hum Mutat 2011
17200672 Fanconi anemia is associated with a defect in the BRCA2 partner PALB2

Livingston, DM, Xia, B, Joenje, H, Wang, W, Llera, J, Dorsman, JC, de Winter, JP, Pals, G, de Vries, Y, Gluckman, E, Ameziane, N, Sheng, Q, Rooimans, MA, Errami, A

Nat Genet 2007
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
19609323 Structural basis for recruitment of BRCA2 by PALB2

Ashworth, A, Pearl, LH, Oliver, AW, Swift, S, Lord, CJ

EMBO Rep 2009
31757951 Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2

Simard, J, Couch, F, Vroling, B, Celosse, N, Stoepker, C, Rodrigue, A, Rother, MB, Wiegant, WW, Vreeswijk, MPG, Boonen, RACM, van Attikum, H, Devilee, P, Sharma, M, Masson, JY

Nat Commun 2019
31636395 Functional characterization of 84 PALB2 variants of uncertain significance

Simard, J, Xia, B, Hu, C, Foo, TK, Carvalho, MA, Rodrigue, A, Belur Nagaraj, A, Gomes, TT, Couch, FJ, Masson, JY, Lee, KY, Wiltshire, T, Monteiro, ANA, Ducy, M

Genet Med 2020
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
31586400 A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor

Milano, L, Simard, J, Montalban, G, Carvalho, MA, Araújo da Silva, W, Coulombe, Y, De-Gregoriis, G, Rodrigue, A, Monteiro, AN, Dellaire, G, Torres Gomes, T, Masson, JY, Ducy, M, da Costa E Silva Carvalho, S, Margaillan, G

Nucleic Acids Res 2019
27899578 COSMIC: somatic cancer genetics at high-resolution

Sondka, Z, Bamford, S, Campbell, PJ, De, T, Kok, CY, Ponting, L, Thompson, S, Jubb, H, Tate, J, Beare, D, Ward, S, Cole, CG, Harsha, B, Boutselakis, H, Bindal, N, Dawson, E, Forbes, SA, Stefancsik, R, Jia, M

Nucleic Acids Res. 2017
  Global Variome shared LOVD PALB2 (partner and localizer of BRCA2)

Tischkowitz, M

   
17200668 PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene

Easton, DF, Hanks, S, Jayatilake, H, Stratton, MR, Barfoot, R, Eccles, D, Kelly, P, Reid, S, Rahman, N, Evans, DG, Seal, S, Elliott, A, Spanova, K, Thompson, D, Renwick, A, Chagtai, T, Breast Cancer Susceptibility Collaboration (UK), -, McGuffog, L

Nat Genet 2007
Participants
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Functional status

Loss of function of PALB2 mutants (BRCA2/RAD51/RAD51C binding) [nucleoplasm]

Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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