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Review
, 1846 (1), 263-75

PALB2: The Hub of a Network of Tumor Suppressors Involved in DNA Damage Responses

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Review

PALB2: The Hub of a Network of Tumor Suppressors Involved in DNA Damage Responses

Jung-Young Park et al. Biochim Biophys Acta.

Abstract

PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.

Keywords: Breast cancer; DNA repair; Genome stability; Homologous recombination; PALB2; Tumor suppressor.

Figures

Figure 1
Figure 1
PALB2 has numerous interactions in its role in mediating DNA damage responses. (A) Three structural domains have been identified, one each in the N-terminal, central, and C-terminal thirds of the protein. (B) Protein interactions with the N-terminal portion of PALB2 (amino acids 1–394) which have been identified are displayed. (C) MRG15, the only known interaction of the central region of PALB2 (amino acids 395–790) with a specific protein, is shown. (D) Numerous proteins with functions in homologous recombination (HR) associate with the WD40 domain present in the C-terminus of PALB2. (B–D) Interacting proteins which have been identified as tumor suppressors are indicated (*).
Figure 2
Figure 2
PALB2 links BRCA1 and BRCA2 into a pathway of products of breast cancer susceptibility genes. This pathway mediates HR, and as a result, the maintenance of genome stability. BRCA1 binds to PALB2 through a coiled-coil motif present on each protein and recruits it to sites of DNA damage. PALB2 then directly binds to the N-terminus of BRCA2 through its WD40 domain and recruits BRCA2. BRCA2 directly binds and recruits the RAD51 recombinase, which mediates strand invasion. PALB2 can also directly bind RAD51, but whether PALB2 can recruit RAD51 independent of BRCA2 is unknown. BRCA1, PALB2, and BRCA2 are all breast cancer susceptibility genes.
Figure 3
Figure 3
Ubiquitin-dependent signaling culminates in the recruitment of PALB2 to sites of DNA damage. (Left) MDC1 binds to the phosphorylated histone variant, H2AX, and is then recognized by the RNF8 E3 ubiquitin ligase. RNF8 mediates polyubiquitination of H2A and of H2AX. (Right) Polyubiquitinated H2A and H2AX are then recognized by RAP80, which has an ubiquitin-interaction motif. The partner of RAP80, Abraxas, is phosphorylated in a cell cycle-dependent manner. BRCA1 binds to phospho-Abraxas, which thereby results in the recruitment of PALB2.
Figure 4
Figure 4
PALB2 and BRCA2 can directly bind RAD51 and pol η. The interaction of PALB2 and BRCA2 with RAD51 promotes formation of a D-loop during strand invasion (left), while interaction with pol η promotes recombination-associated DNA synthesis (right). PALB2 and BRCA2 may thereby coordinate these two steps during HR.

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