Abstract
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.
Highlights
DNA is constantly damaged by genotoxic factors and intracellular metabolic processes
The latter is achieved through interaction with the transcription factor MRG15 (Morf-related gene on chromosome 15), which is a part of many transcriptional regulator complexes such as the HAT-associated Tip60/NuA4 complex and the HDAC-associated Sin3S/Rpd3S complex [15,16,17,18]
In order to define the mechanism of Partner and localizer of BRCA2 (PALB2) interaction with transcription complexes, we solved the crystal structure of the MRG15 MRG domain bound to a PALB2 peptide
Summary
DNA is constantly damaged by genotoxic factors and intracellular metabolic processes. PALB2 interacts with nucleosomes and with transcription factors tethering DNA repair machinery to chromatin and connecting it with transcription The latter is achieved through interaction with the transcription factor MRG15 (Morf-related gene on chromosome 15), which is a part of many transcriptional regulator complexes such as the HAT-associated Tip60/NuA4 complex and the HDAC-associated Sin3S/Rpd3S complex [15,16,17,18]. These and other MRG15 complexes are critical for cell proliferation, embryonic development, DNA damage repair, and alternative splicing [15,17,18,19,20,21,22,23,24,25,26,27,28,29]. The role of key interaction amino acids and known cancer-associated PALB2 mutations was assayed through solution binding studies
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