The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction.

Abstract

Tumor suppressor Partner and Localizer of BRCA2 (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.

A double-ring of human RAD52 remodels replication forks restricting fork reversal

“…The most significant difference is that the RAD52-mediated strand exchange is confined to the gap region and is not followed up by the branch migration. Recently, the ability to carry out DNA and DNA/RNA strand exchange reaction was found in the intrinsically disordered DNA binding region of tumor suppressor PALB2 (partner and localizer of BRCA2) extending the range of facilitators of this important cellular process 47,48 .…”

Genetics risk assessment of PALB2 polymorphism (rs249954 and rs152451) with breast cancer susceptibility among the Pashtun population of Khyber Pakhtunkhwa, Pakistan

“…PALB2 is an 1186 amino acid protein located on chromosome 16p12 and with a molecular weight of approximately 130 kilo Daltons, consisting of 12 intron and 13 exons [16]. PALB2 contains several proteins including Nterminal coiled-coil domain that interacts with BRCA1 at its C terminus and the WD40 domain that interacts with BRCA2 at the Chromatin organization Motif to promote chromatin organization [17][18][19]. PALB2 provides an association between BRCA1 and BRCA2 in the DNA damage repair [20].…”