Abstract
BReast Cancer Associated proteins 1 and 2 (BRCA1, -2) and Partner and Localizer of BRCA2 (PALB2) protein are tumour suppressors linked to a spectrum of malignancies, including breast cancer and Fanconi anemia. PALB2 coordinates functions of BRCA1 and BRCA2 during homology-directed repair (HDR) and interacts with several chromatin proteins. In addition to protein scaffold function, PALB2 binds DNA. The functional role of this interaction is poorly understood. We identified a major DNA-binding site of PALB2, mutations in which reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%. PALB2 N-terminal DNA-binding domain (N-DBD) stimulates the function of RAD51 recombinase. Surprisingly, it possesses the strand exchange activity without RAD51. Moreover, N-DBD stimulates the inverse strand exchange and can use DNA and RNA substrates. Our data reveal a versatile DNA interaction property of PALB2 and demonstrate a critical role of PALB2 DNA binding for chromosome repair in cells.
Highlights
Breast cancer associated proteins 1 and 2 (BRCA1, À2) regulate an efficient non-mutagenic pathway of chromosome break repair and are described as guardians of chromosomal integrity (Venkitaraman, 2014)
Similar to the previously published finding that the full length Partner and Localizer of BRCA2 (PALB2) stimulates RAD51 function (Buisson et al, 2010; Dray et al, 2010), we found that the PALB2 N-terminal DNA-binding domain (N-DNA binding domains (DBDs)) alone stimulates RAD51-mediated strand exchange (Figure 4)
We identified major DNA-binding residues of PALB2 and demonstrated their critical role for homologydirected repair (HDR) in cells
Summary
Breast cancer associated proteins 1 and 2 (BRCA1, À2) regulate an efficient non-mutagenic pathway of chromosome break repair and are described as guardians of chromosomal integrity (Venkitaraman, 2014) They initiate RAD51-mediated homologous recombination (HR) (Davies et al, 2001; Moynahan et al, 2001; Sharan et al, 1997; Venkitaraman, 2000) and facilitate restart of stalled replication (Badie et al, 2010; Lomonosov et al, 2003; Schlacher et al, 2011). The PALB2 C-terminal WD40 domain interacts with BRCA2 (Oliver et al, 2009; Xia et al, 2006) while the N-terminus forms a complex with BRCA1 (Zhang et al, 2009a; Zhang et al, 2009b) The latter localizes at double-stranded DNA break (DSB) sites at earlier stage of repair, inhibiting an alternative pathway of non-homologous end joining and initiating homologydirected repair (HDR) through recruitment of PALB2/BRCA2/RAD51 (Prakash et al, 2015)
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