The PALB2 DNA binding domain is an intrinsically disordered recombinase.

Tumor suppressor Pa rtner and L ocalizer of B RCA 2 (PALB2) is a scaffold protein that links BRCA1, BRCA2 and other DNA repair factors and plays a crucial role in homologous recombination (HR). The interaction of PALB2 with DNA strongly enhances the efficiency of HR. Importantly, the PALB2 DNA-binding domain (PALB2-DBD) supports strand exchange of DNA or RNA, a complex multistep reaction carried by only a few protein families like RecA-like recombinases or Rad52. The mechanisms of PALB2 DNA binding and strand exchange are unknown. Through circular dichroism, electron paramagnetic spectroscopy and small-angle X-ray scattering, we found that the PALB2-DBD is intrinsically disordered, even when bound to DNA. Intrinsically disordered proteins (IDPs) are prevalent in the human proteome and have many important biological functions. The advanced level of complexity of the strand exchange reaction significantly expands the functional repertoire of IDPs. Using confocal single-molecule FRET, we found that PALB2-DBD binding leads to oligomerization-dependent compaction of DNA. We hypothesize that PALB2-DBD uses a "chaperone-like" mechanism to aid formation and resolution of complex DNA and RNA multichain intermediates during DNA replication and repair. Similar DNA-binding IDRs may represent a novel class of functional domains evolved in eukaryotic nucleic acids metabolism complexes.