Abstract
Mutations in the BRCA2 tumor suppressor protein leave individuals susceptible to breast, ovarian and other cancers. The BRCA2 protein is a critical component of the DNA repair pathways in eukaryotes, and also plays an integral role in fostering genomic variability through meiotic recombination. Although present in many eukaryotes, as a whole the BRCA2 gene is weakly conserved. Conserved fragments of 30 amino acids (BRC repeats), which mediate interactions with the recombinase RAD51, helped detect orthologs of this protein in other organisms. The carboxy-terminal of the human BRCA2 has been shown to be phosphorylated by checkpoint kinases (Chk1/Chk2) at T3387, which regulate the sequestration of RAD51 on DNA damage. However, apart from three BRC repeats, the Drosophila melanogaster gene has not been annotated and associated with other functionally relevant sequence fragments in human BRCA2. In the current work, the carboxy-terminal phosphorylation threonine site (E=9.1e-4) and a new BRC repeat (E=17e-4) in D. melanogaster has been identified, using a fragmented alignment methodology (FRAGAL). In a similar study, FRAGAL has also identified a novel half-a- tetratricopeptide (HAT) motif (E=11e-4), a helical repeat motif implicated in various aspects of RNA metabolism, in Utp6 from yeast. The characteristic three aromatic residues with conserved spacing are observed in this new HAT repeat, further strengthening my claim. The reference and target sequences are sliced into overlapping fragments of equal parameterized lengths. All pairs of fragments in the reference and target proteins are aligned, and the gap penalties are adjusted to discourage gaps in the middle of the alignment. The results of the best matches are sorted based on differing criteria to aid the detection of known and putative sequences. The source code for FRAGAL results on these sequences is available at https://github.com/sanchak/FragalCode, while the database can be accessed at www.sanchak.com/fragal.htm l.
Highlights
The breast cancer susceptibility protein BRCA2, first identified in 19951, is a critical recombinase regulator[2] that ensures genomic stability through high fidelity repair[3,4] of double stranded breaks (DSB) and prevents stalled replication forks from replicating[5] in the DNA
Breast cancer susceptibility protein BRCA2 The D. melanogaster gene (CG30169)[41] encodes a 971 amino acid protein, and contains three BRC repeat units[8,14]
The hBRCA2 protein is annotated for several sites phosphorylated by checkpoint kinases, which regulate its interaction with RAD519,10
Summary
The breast cancer susceptibility protein BRCA2, first identified in 19951, is a critical recombinase regulator[2] that ensures genomic stability through high fidelity repair[3,4] of double stranded breaks (DSB) and prevents stalled replication forks from replicating[5] in the DNA. The BRC repeats have helped identify BRCA2 orthologs in various eukaryotic species[14] Functional characterization of this gene in Drosophila melanogaster has demonstrated its interaction with RAD51, and a critical role in mitotic and meiotic DNA repair as well as homologous recombination[11,15]. RAD51 shows varying affinity for the different BRC motifs[18,19] This difference in repeat numbers in Drosophila has raised doubts whether ‘this higher repeat number is real or a genome mis-assembly artifact’[20], and led to speculation on the evolution of these closely related organisms[17,20]. Any such hypothesis would need to be revisited if a new BRC motif were to be identified in D. melanogaster
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