Search results for BRCA2

Showing 22 results out of 60

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Protein (5 results from a total of 16)

Identifier: R-HSA-50951
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: BRCA2: P51587
Identifier: R-HSA-5685241
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: BRCA2: P51587
Identifier: R-HSA-419548
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PALB2: Q86YC2
Identifier: R-HSA-9704437
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PALB2: Q86YC2
Identifier: R-HSA-9704820
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PALB2: Q86YC2

Interactor (1 results from a total of 1)

Identifier: BRCA2
Species: Homo sapiens
Primary external reference: UniProt: BRCA2

Reaction (5 results from a total of 12)

Identifier: R-HSA-5685242
Species: Homo sapiens
Compartment: nucleoplasm
CHEK1 phosphorylates BRCA2 on threonine residue T3887, in the C-terminal region of BRCA2. CHEK1-mediated BRCA2 phosphorylation, as well as CHEK1 mediated RAD51 phosphorylation, promotes the association of BRCA2 with RAD51 (Bahassi et al. 2008).
Identifier: R-HSA-5693620
Species: Homo sapiens
Compartment: nucleoplasm, chromosome
A D-loop structure is formed when complementary duplex DNA (sister chromatid arm) is progressively invaded by the RAD51 nucleoprotein filament, with base pairing of the invading ssDNA and the complementary sister chromatid DNA strand (Sung et al. 2003). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity, thus enhancing RAD51-mediated strand exchange (branch migration) and promoting the formation of D-loop structures (synaptic complex assembly). PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). The direct BRCA1 interaction with PALB2 helps to fine-tune the localization of BRCA2 and RAD51 at DNA double-strand breaks (DSBs) (Zhang et al. 2009, Sy et al. 2009). 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).
Identifier: R-HSA-5693561
Species: Homo sapiens
Compartment: nucleoplasm
BRCA2 and RAD51 interact directly through the highly conserved BRCT repeats in BRCA2 (Venkitaraman 2002). CHEK1-mediated phosphorylation of BRCA2 (at threonine residue T3387) and RAD51 (at threonine residue T309) facilitates their binding (Sorensen et al. 2005, Bahassi et al. 2008). One BRCA2 can bind up to six RAD51 molecules, thus playing an important role in RAD51 nucleation at the dsDNA-ssDNA junction created by resection of DNA double-strand breaks (DSBs) (Liu et al. 2010, Thorslund et al. 2010, Jensen et al. 2010). After the nucleation step, additional RAD51 molecules bind the ssDNA and multimerize, forming RAD51 nucleoprotein filaments (Yang et al. 2005). BRCA2-mediated RAD51 loading displaces the RPA complex from 3' overhanging ssDNA at DSBs (Sugiyama et al. 1997, Jensen et al. 2010), presumably with other RPA-bound proteins, such as ATR:ATRIP and complexes involved in ATR catalytic activation.
Identifier: R-HSA-9704408
Species: Homo sapiens
Compartment: nucleoplasm
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).
Identifier: R-HSA-9704330
Species: Homo sapiens
Compartment: nucleoplasm
The coiled-coil domain at the N-terminus of PALB2 represents a hotspot for mutations in PALB2. Several PALB2 missense mutants have been characterized either in targeted studies (Sy et al. 2009, Foo et al. 2017, Song et al. 2018) or as part of high throughput approaches to characterize clinical variants of uncertain significance (reviewed in Boonen et al. 2020).

The following PALB2 missense mutants have been shown to be at least partially defective in their ability to bind to BRCA1 (some of these mutants were also shown to be defective in their ability to homodimerize and to promote homologous recombination repair (HRR); in addition, some have been shown to confer sensitivity to DNA damaging agents or to PARP inhibitors):
PALB2 L21A (originally studied as a synthetic mutant with an amino acid substitution at one of the coiled-coil domain residues of PALB2 that are critical for BRCA1 binding and homodimerization (Sy et al. 2009, Song et al. 2018); this mutant has also been reported clinically, in Clingen Allele Registry (Pawliczek et al. 2018), as a consequence of an in-frame indel in PALB2)
PALB2 L24S (Boonen et al. 2019; Wiltshire et al. 2020; also shown to be defective in HRR (Boonen et al. 2019, Wiltshire et al. 2020), confer sensitivity to cisplatin (Wiltshire et al. 2020) and PARP inhibitor olaparib (Wiltshire et al. 2020))
PALB2 Y28C (partially impaired in BRCA1 binding, Foo et al. 2017; significantly impaired BRCA1 binding, Rodrigue et al. 2019; does not disrupt PALB2 self-interaction (Foo et al. 2017); not significantly defective in HRR and does not confer sensitivity to DNA damaging agents and PARP inhibitors (Foo et al. 2017); partially defective in HRR (Rodrigue et al. 2019, Wiltshire et al. 2020) and significantly sensitive to cisplatin and PARP inhibition (Boonen et al. 2019))
PALB2 L35P (Foo et al. 2017, Rodrigue et al. 2019, Boonen et al. 2019, Wiltshire et al. 2020; does not disrupt PALB2 self-interaction (Foo et al. 2017); also shown to be defective in HRR (Foo et al. 2017, Rodrigue et al. 2019, Boonen et al. 2019, Wiltshire et al. 2020), confer sensitivity to platinum salts (Foo et al. 2017, Boonen et al. 2019, Wiltshire et al. 2020), and confer sensitivity to PARP inhibitors (Foo et al. 2017, Boonen et al. 2019, Wiltshire et al. 2020))
PALB2 R37H (not significantly affected in BRCA1 binding, Foo et al. 2017; partially impaired in BRCA1 binding, Boonen et al. 2019; partially defective in HRR (Foo et al. 2017, Rodrigue et al. 2019, Boonen et al. 2019, Wiltshire et al. 2020))

Interestingly, some of the PALB2 variants that show a defective interaction with BRCA1, such as PALB2 L24S, PALB2 Y28C, and PALB2 L35P, seem to have slightly elevated protein levels (Foo et al. 2017, Boonen et al. 2019, Wiltshire et al. 2020).

Synthetic PALB2 mutants generated by directed mutagenesis, PALB2 L21P (Zhang et al. 2009), PALB2 L24P (Zhang et al. 2009), PALB2 Y28A (Sy et al. 2009) and PALB2 L35A (Sy et al. 2009) are also unable to bind BRCA1 and show impaired homologous recombination function.

The following PALB2 mutants, reported in cancer and predicted to be pathogenic, have not been functionally studied and are annotated as candidate loss-of-function mutants for BRCA1 binding based on their sequence similarity with functionally studied PALB2 mutants:
PALB2 L21F (similar to PALB2 L21A)
PALB2 L35F (similar to the synthetic mutant PALB2 L35A, described by Sy et al. 2009 and to the functionally characterized cancer-associated mutant PALB2 L35P)
PALB2 R37C (similar to PALB2 R37H)
PALB2 E12* (truncation mutants that lacks the coiled coil domain involved in BRCA1 binding, which maps to residues 9-42, as described by Sy et al. 2009; this truncation mutant may be a null mutant as the protein is predicted to have only the first 11 amino acids).

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).

Complex (5 results from a total of 18)

Identifier: R-HSA-5693545
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5685655
Species: Homo sapiens
Compartment: nucleoplasm

Set (1 results from a total of 1)

Identifier: R-HSA-9704406
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (5 results from a total of 12)

Identifier: R-HSA-9704646
Species: Homo sapiens
Compartment: nucleoplasm
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).
Identifier: R-HSA-5693616
Species: Homo sapiens
Compartment: nucleoplasm
The presynaptic phase of homologous DNA pairing and strand exchange during homologous recombination repair (HRR) begins with the displacement of RPA from ssDNA (Thompson and Limoli 2003) by the joint action of RAD51 and BRCA2. CHEK1-mediated phosphorylation of RAD51 and BRCA2 (Sorensen et al. 2005, Bahassi et al. 2008) is needed for BRCA2-mediated nucleation of RAD51 on 3'-ssDNA overhangs, RPA displacement and formation of RAD51 nucleofilaments (Yang et al. 2005, Jensen et al. 2010, Liu et al. 2010, Thorslund et al. 2010). Invasive RAD51 nucleofilaments are stabilized by the BCDX2 complex composed of RAD51B, RAD51C, RAD51D and XRCC2 (Masson et al. 2001, Chun et al. 2013, Amunugama et al. 2013).
Identifier: R-HSA-5693579
Species: Homo sapiens
Compartment: nucleoplasm
The presynaptic phase of homologous DNA pairing and strand exchange begins with the displacement of RPA from 3'-ssDNA overhangs created by extensive resection of DNA double-strand break (DSB) ends. RPA is displaced by the joint action of RAD51 and BRCA2. BRCA2 nucleates RAD51 on 3'-ssDNA overhangs, leading to formation of invasive RAD51 nucleofilaments which are stabilized by the BCDX2 complex (RAD51B:RAD51C:RAD51D:XRCC2). Stable synaptic pairing between recombining DNA molecules involves the invasion of the homologous sister chromatid duplex DNA by the RAD51 nucleofilament and base-pairing between the invading ssDNA and the complementary sister chromatid DNA strand, while the non-complementary strand of the sister chromatid DNA duplex is displaced. This results in the formation of a D-loop structure (Sung et al., 2003). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity and D-loop formation. PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 also interacts with BRCA1, and this interaction fine-tunes the localization of BRCA2 and RAD51 at DNA DSBs (Zhang et al. 2009, Sy et al. 2009). The CX3 complex, composed of RAD51C and XRCC3, binds D-loop structures through interaction with PALB2 and may be involved in the resolution of Holliday junctions (Chun et al. 2013, Park et al. 2014).

While RAD52 promotes formation of invasive RAD51 nucleofilaments in yeast, human BRCA2 performs this function, while human RAD52 regulates single strand annealing (SSA) (reviewed by Ciccia and Elledge 2010).

Identifier: R-HSA-9701192
Species: Homo sapiens
Compartment: nucleoplasm
In addition to its role in DNA double-strand break (DSB) signaling, BRCA1 plays an important role in homologous recombination repair (HRR) of DSBs by directly promoting recruitment of PALB2 and indirectly BRCA2 to DSB repair sites. In addition, BRCA1 increases the speed and processivity of DNA end resection which consists of 5′–3′ nucleolytic degradation of DSBs (Cruz-Garcia et al. 2014). The direct BRCA1 interaction with PALB2 helps to fine-tune the localization of BRCA2 and RAD51 at DSBs (Zhang et al. 2009, Sy et al. 2009). PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity, thus enhancing RAD51-mediated strand exchange (branch migration) and promoting the formation of D-loop structures (synaptic complex assembly). A D-loop structure is formed when complementary duplex DNA (sister chromatid arm) is progressively invaded by the RAD51 nucleoprotein filament, with base pairing of the invading ssDNA and the complementary sister chromatid DNA strand (Sung et al. 2003).

The N-terminal region of BRCA1 contains the RING domain (residues 7-98), required for the heterodimerization of BRCA1 with BARD1. BRCA1:BARD1 heterodimer has E3 ubiquitin ligase activity which is important for DNA repair (Drost et al. 2011). Several missense mutations within the RING domain have been linked to increased risks of developing breast/ovarian cancers (Bouwman et al. 2013; Starita et al. 2018). BRCA1 mutant proteins impaired in BARD1 binding are annotated in the pathway "Defective DNA double strand break response due to BRCA1 loss of function".

The C-terminal region of BRCA1 which contains two coiled coil domains (residues 1397-1424) and two BRCT domains (residues 1642-1736 for BRCT 1; residues 1756-1855 for BRCT 2) is involved in PALB2 binding, with the second coiled coil domain being essential (Sy et al. 2009). Several cancer-associated BRCA1 missense mutants that affect the C-terminal region were shown to have reduced ability to bind PALB2 (Sy et al. 2009). In addition, many nonsense and frameshift mutations in BRCA1 reported in cancer result in truncated proteins that lack the PALB2-binding domain.
Identifier: R-HSA-9701193
Species: Homo sapiens
Compartment: nucleoplasm
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.
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