Note | PALB2 has a large number of interactions with other DNA damage response proteins that function in DNA repair by homologous recombination, as illustrated below and reviewed elsewhere (Park et al., 2014b). This includes interactions with BRCA1, BRCA2, RAD51, RAD51C and XRCC3. In this way, PALB2 functions in a large network of HR proteins and seems to have a key role in coordinating their function (Park et al., 2014b). In particular, direct binding to BRCA1 mediates PALB2 recruitment to DNA damage foci (Zhang et al., 2009a; Zhang et al., 2009b). Notably, KEAP1-dependent ubiquitination of the PALB2 coiled-coil domain suppresses HR in G1 by inhibiting the interaction of PALB2 with BRCA1 (Orthwein et al., 2015). Importantly, direct interactions of the N- and C-termini of PALB2 with BRCA1 and BRCA2, respectively, physically links these tumor suppressor proteins (Sy et al., 2009b; Zhang et al., 2009a; Zhang et al., 2009b). PALB2 also directly interacts with MORF4L1 (MRG15); this interaction appears to be independent of the interaction of MRG15 with the TIP60 histone methyltransferase complex (Hayakawa et al., 2010; Sy et al., 2009a). Additionally, PALB2 interacts with KEAP1, a sensor of oxidative stress (Ma et al., 2012). PALB2 is essential for embryonic development; homozygous knockout of PALB2 in mice disrupts the normal differentiation of mesoderm and results in embryonic lethality by E9.5 (Bowman-Colin et al., 2013; Rantakari et al., 2010). |
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Description | PALB2 contains a coiled-coil domain at its N-terminus from amino acids (a.a.) 9-44, which mediates interaction with BRCA1 (Sy et al., 2009b; Zhang et al., 2009a; Zhang et al., 2009b). A nearby sequence present at a.a. 88-94 in human PALB2 is responsible for interaction with KEAP1 (Ma et al., 2012). PALB2 contains a Chromatin Association Motif (ChAM) from a.a. 395-446 and a FXLP mofif from a.a. 612-615, which binds to MRG15, thereby promoting the interaction of PALB2 with chromatin (Bleuyard et al., 2012; Hayakawa et al., 2010; Xie et al., 2012). The C-terminal WD40 domain of PALB2, from a.a. 867-1186, directly binds BRCA2 (Oliver et al., 2009), RAD51 (Buisson et al., 2010), RAD51C and XRCC3 (Park et al., 2014a), POLE (pol η) (Buisson et al., 2014) and RNF168 (Luijsterburg et al., 2017). Within the WD40 domain, there is a hidden nuclear protein export signal from a.a. 928-945 (Pauty et al., 2017). |
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| Key domains in the PALB2 protein and interactions they mediate. Functional domains (or motifs) are shown in black and are identified above the diagram; the amino acids that each domain spans is noted in parentheses. Known interactions which are mediated by the particular domain or motif are shown beneath the diagram. |
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Expression | According to The Human Protein Atlas (online), PALB2 is ubiquitously expressed to varying degrees across different tissues including the brain, bone marrow, spleen, lung, liver, pancreas, stomach, kidney, testis, ovary and skin. |
Localisation | PALB2 localises to nuclei in both chromatin and the nucleoplasm during interphase (Xia et al., 2006). In untreated populations of human cancer cells, the majority of cells display a dispersed non-nucleolar signal while a subset of cells also display DNA damage foci. Treatment with agents that induce DNA damage and/or replication stress increases the assembly of nuclear DNA damage foci. The assembly of PALB2 nuclear foci requires interaction of the protein with BRCA1 (Zhang et al., 2009a; Zhang et al., 2009b). Additionally, the recruitment of PALB2 into foci is also promoted by MDC1, RNF8, UIMC1 (RAP80) and ABRAXAS1 (Abraxas), all of which are involved in the recruitment of BRCA1 (Zhang et al., 2012), and by RNF168 (Luijsterburg et al., 2017). MRG15, PALB2 phosphorylated at S59 and hypophosphorylated at S64, the APRIN cohesion factor and phosphorylated RPA2 also promote the recruitment of PALB2 to sites of DNA damage (Brough et al., 2012; Buisson et al., 2017; Hayakawa et al., 2010; Murphy et al., 2014). |
Function | PALB2 acts as a typical cancer suppressor gene. Mono-allelic loss-of-function germline mutations are associated with an increased risk of developing breast cancer (Antoniou et al., 2014; Erkko et al., 2007; Rahman et al., 2007) and pancreatic cancer (Jones et al., 2009). Bi-allelic mutations in PALB2 (FANCN) cause a severe form of Fanconi anemia, subtype FA-N, with early onset of acute myeloid leukemia, medulloblastoma, neuroblastoma and often Wilms' tumor, leading to early death in the first decade of life (Reid et al., 2007). PALB2 is believed to act as a tumor suppressor protein by mediating DNA repair and thereby suppressing genome instability (Park et al., 2014b). Importantly, PALB2/FANCN-deficient cells have largely reduced levels of wild-type BRCA2 protein (Xia et al., 2007; Xia et al., 2006), reflective of a role for PALB2 in stabilizing the BRCA2 protein. Therefore, the phenotypes of these cells, as well as the clinical phenotypes of FA-N patients, are very similar to those of cells from patients with a BRCA2/ FANCD1 deficiency. As demonstrated by employing reporter constructs integrated into human cells, PALB2 has an important role in mediating the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) (Xia et al., 2006). While not specifically tested for PALB2, its partner BRCA2 has an additional role in mediating HR in response to DNA interstrand crosslinks (ICLs); ICLs are specifically repaired by FA proteins (Nakanishi et al., 2011). Consistent with a requirement for PALB2 in DNA repair by HR, and due to largely reduced BRCA2 protein levels, PALB2-deficient cells are hypersensitive to DNA interstrand crosslinking agents such as mitomycin C (MMC) and cisplatin (Xia et al., 2007; Xia et al., 2006), and to ionizing radiation (IR) (Park et al., 2014a). As further support for a role in DNA repair, PALB2-deficient cells are also hypersensitive to poly-ADP ribose polymerase (PARP) inhibitors (Buisson et al., 2010) and to aldehydes (Ghosh et al., 2014). As a mediator of HR, PALB2 recruits BRCA2 and the RAD51 recombinase to sites of DNA damage (Xia et al., 2006). Additionally, PALB2 stabilizes BRCA2 present in chromatin (Xia et al., 2006). Biochemical experiments demonstrate that PALB2 also directly binds DNA and promotes strand invasion necessary to initiate HR (Buisson et al., 2010; Dray et al., 2010). In this process, PALB2 decreases inhibition of D-loop formation mediated by RPA and enhances HR by stabilizing RAD51 filaments. Also, PALB2 interacts with pol η, thereby promoting DNA synthesis at D-loops (Buisson et al., 2014). PALB2 has additional roles in other facets of the DNA damage response, beyond its role in mediating HR. Among these, PALB2 promotes maintenance of G2 checkpoint arrest in response to DNA damage (Menzel et al., 2011). PALB2 is also required for chromosome stability. PALB2-deficient cells display increased breaks and radials in response to DNA damage (Bowman-Colin et al., 2013). Further, PALB2 has a role in protecting the cell from replication stress. Carriers of PALB2 mutations display increased firing of dormant replication origins (Nikkila et al., 2013) and mice with a single amino acid knock-in of in Brca2, p.Gly25Arg, which is deficient for binding to PALB2, display decreased fork stability in response to hydroxyurea (Hartford et al., 2016). Homozygosity of these Brca2 knock-in mice, and also hemizygosity in combination with Palb2 and Trp53 heterozygosity, results in defects in body size, fertility, meiosis and genome stability, and also increases tumor susceptibility (Hartford et al., 2016). Further, via its chromodomain, MRG15 targets PALB2 to actively transcribed genes and protects them from DNA damage induced by camptothecin (Bleuyard et al., 2017). |
Homology | Based on HomoloGene (NCBI), the following are homologs of the human PALB2 gene (NP_078951.2, 1186 a.a.): Chimpanzee (Pan troglodytes) XP_510877.2, 1186 a.a. Rhesus monkey (Macaca mulatta) XP_001095569.2, 1135 a.a. Dog (Canis lupus familiaris) XP_850671.2, 1195 a.a. Mouse (Mus musculus) NP_001074707.1, 1104 a.a. Rat (Rattus norvegicus) NP_001178532.1, 1110 a.a. Chicken (Gallus gallus) XP_004945321.1, 1341 a.a. |
MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress |
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Proc Natl Acad Sci U S A 2017 Jul 18;114(29):7671-7676 |
PMID 28673974 |
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Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer |
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PMID 23657012 |
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APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer |
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EMBO J 2012 Mar 7;31(5):1160-76 |
PMID 22293751 |
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Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination |
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Nat Struct Mol Biol 2010 Oct;17(10):1247-54 |
PMID 20871615 |
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Mol Cell 2017 Jan 19;65(2):336-346 |
PMID 28089683 |
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Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer |
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Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2 |
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Hypersensitivities for acetaldehyde and other agents among cancer cells null for clinically relevant Fanconi anemia genes |
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PLoS Genet 2016 Aug 4;12(8):e1006236 |
PMID 27490902 |
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PMID 25225577 |
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MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks |
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J Cell Sci 2010 Apr 1;123(Pt 7):1124-30 |
PMID 20332121 |
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Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene |
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A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation |
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PMID 28240985 |
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PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function |
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Mol Cell Biol 2012 Apr;32(8):1506-17 |
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A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance |
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Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery |
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J Cell Biol 2014 Aug 18;206(4):493-507 |
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PMID 29198440 |
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Heterozygous mutations in PALB2 cause DNA replication and damage response defects |
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PMID 24153426 |
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PMID 26649820 |
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Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair |
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PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2 |
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