The tumor suppressor protein partner and localizer of BRCA2 (PALB2) orchestrates the interactions between breast cancer susceptibility proteins 1 and 2 (BRCA1, -2) that are critical for genome stability, homologous recombination (HR) and DNA repair. PALB2 mutations predispose patients to a spectrum of cancers, including breast and ovarian cancers. PALB2 localizes HR machinery to chromatin and links it with transcription through multiple DNA and protein interactions. This includes its interaction with MRG15 (Morf-related gene on chromosome 15), which is part of many transcription complexes, including the HAT-associated and the HDAC-associated complexes. This interaction is critical for PALB2 localization in actively transcribed genes, where transcription/replication conflicts lead to frequent replication stress and DNA breaks. We solved the crystal structure of the MRG15 MRG domain bound to the PALB2 peptide and investigated the effect of several PALB2 mutations, including patient-derived variants. PALB2 interacts with an extended surface of the MRG that is known to interact with other proteins. This, together with a nanomolar affinity, suggests that the binding of MRG15 partners, including PALB2, to this region is mutually exclusive. Breast cancer-related mutations of PALB2 cause only minor attenuation of the binding affinity. New data reveal the mechanism of PALB2-MRG15 binding, advancing our understanding of PALB2 function in chromosome maintenance and tumorigenesis.

This study aims to determine whether astronauts who have not flown in space can provide an unbiased comparison to astronauts who have flown in space when analyzing long-term health outcomes such as incidence of chronic disease and mortality. Various propensity score methods failed to achieve good balance between groups, demonstrating that even with sophisticated rebalancing methods the group of non-flight astronauts cannot be demonstrated to be an unbiased comparison group for examining the effect of the hazards of spaceflight on incidence and mortality from chronic diseases.

PALB2 (Partner and Localizer of BRCA2) is recombination mediator protein (RMP) involved in homology dependent repair (HDR) of double strand breaks (DSB). PALB2 works synergistically with BRCA2 by promoting Rad51 recombinase filament formation on single‐stranded (ss) DNA to initiate strand exchange essential for HDR. Numerous inherited PLAB2 mutations are reported to predispose to cancers such as breast and pancreatic cancers and rare genetic disease, Fanconi Anemia. However, the molecular mechanism PALB2 function is not well characterized. Here we report the DNA binding properties of PALB2 DNA‐binding domain (DBD), affinity and stoichiometry of interaction with various DNA substrates and identify residues involved in DNA binding. Further, we report an unanticipated activity of PALB2, where PALB2 promoted strand exchange in the absence of recombinase. This activity was enhanced in the presence of recombinase Rad51 and is abolished upon mutations of PALB2 DNA‐binding residues. Several properties also resemble those reported for Rad52. Our study demonstrates that PALB2 has multiple roles in homologous DNA repair.Support or Funding InformationSiteman Cancer centerThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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