Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Abstract

Partner and localizer of BRCA2 (PALB2) is vital for homologous recombination (HR) repair in response to DNA double-strand breaks (DSBs). PALB2 functions as a tumor suppressor and participates in the maintenance of genome integrity. In this review, we summarize the current knowledge of the biological roles of the multifaceted PALB2 protein and of its regulation. Moreover, we describe the link between PALB2 pathogenic variants (PVs) and breast cancer predisposition, aggressive clinicopathological features, and adverse clinical prognosis. We also refer to both the opportunities and challenges that the identification of PALB2 PVs provides in breast cancer genetic counseling and precision medicine.

Keywords: PALB2; breast cancer; homologous recombination; pathogenic variants; precision medicine.

Figure 1

The role of PALB2 in homologous recombination (HR). In response to DNA double-strand breaks (DSBs) induced by genotoxic agents in the S/G2 phase, the Mre11–RAD50–Nbs1 (MRN) complex is recruited to DSBs and promotes ATM recruitment. The inactive ATM dimer then dissociates into active monomers through autophosphorylation at serine 1981. Active ATM monomers phosphorylate H2AX in regions of DSBs and create a platform to recruit BRCA1, which facilitates a shift from non-homologous end-joining to HR. Meanwhile, CtBP-interacting protein (CtIP), in conjunction with the MRN complex, catalyzes 5′-3′ resection at DSBs to generate single-stranded DNA (ssDNA), and further resection is completed by Exo1 exonuclease and Dna2 nuclease/helicase in cooperation with BLM helicase. The resulting ssDNA is then covered by replication protein A (RPA). PALB2 is phosphorylated on S59 by ATR/Chk1, which accelerates its recruitment to sites of damage. Thereafter, BRCA2 is recruited by PALB2. PALB2 and BRCA2 further promote RPA removal and RAD51 loading. The resulting RAD51-ssDNA filament invades the intact sister chromatid and extends the strand with the help of DNA polymerase δ/η/κ. Finally, further restoration and ligation of double strands are carried out.

Figure 2

Schematic representation of the PALB2 protein and the position of functionally validated PALB2 pathogenic missense variants. The structural motifs and functional domains of PALB2. C.C.: coiled-coil motif (9–42); ETGE motif (88–94); ChAM: chromatin-association motif (395–446); WD40: WD40-repeats (853–1186); NES: nuclear export sequence (928–945). The validated pathogenic missense variants are marked on top. The only recognized PALB2 pathogenic missense variant (p.L35P) validated by systematic in vitro functional assays is highlighted in red.

Figure 3

The multifaceted functions of PALB2 and its regulation. (A) PALB2 is recruited through the SETD2/H3K36me3/MRG15 axis and protects transcriptionally active genes from replication stress. (B) PALB2 promotes NRF2 function during oxidative stress by competitively binding KEAP1. (C) Following ionizing radiation (IR), the switch from PALB2 oligomerization to BRCA1-PALB2 interaction is regulated by S988 phosphorylated BRCA1. (D) Phosphorylation events in PALB2 regulation. In the resection phase, high CDKs induce PALB2 phosphorylation at S64, inhibiting its interaction with BRCA1, whereas in post-resection phase, ATR-induced PALB2 phosphorylation at S59 promotes BRCA1-PALB2 binding and enhances HR activity. (E) In the G1 phase of the cell cycle, PALB2 is ubiquitylated by the CUL3–KEAP1 complex, which disrupts BRCA1-PALB2 interaction, whereas in the G2 phase, PALB2 ubiquitylation is neutralized by USP11. (F) RNF168 mediates PALB2 recruitment and RAD51 loading in BRCA1-deficient cells.