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Danilowicz, C.

Publications and source records attributed to Danilowicz, C..

3 recordsLinked to original sources

Mechanical response of the RecA nucleoprotein filament to increasing D-loop length

AO_SCPLOWBSTRACTC_SCPLOWProtein filaments play fundamental functions in the cell, ranging from scaffolding like in the cytoskeleton to sensing and transmitting forces and torques. Here we address the case of the nucleoprotein filaments (NPFs) of homologous recombination (HR) formed by the polymerization of the RecA protein on DNA. In contrast to the cytoskeleton filaments, the HR filaments are not known to exert or sense forces. However the stress in the stretched and unwound DNA bound to those filaments was shown to play a role in promoting DNA strand exchange during the early stage of the HR mechanism. Here we use molecular dynamics simulations to examine whether the strain in the nucleoprotein filament upon strand exchange progression and D-loop formation may influence subsequent steps of the HR process. Our results indicate that the filament mechanical properties are sensitive to the length of DNA incorporated in the D-loop. The response we observe upon increasing the D-loop length is first elastic, up to a threshold that we estimate to be 27 incorporated base pairs, after which the NPF enters a new stage where the protein-DNA connectivities are reorganized. Notably, the DNA displaced strand locally switches from site II to site III, a newly characterized binding site. We discuss the possible consequence of this mechanical response of the NPFs for the course of the HR process.

molecular biology↗

RecA balances genomic stability and evolution using many successive mismatch tolerant homology tests

A double-strand break (DSB) must usually be repaired with as little alteration to the genome as possible, though some rare alterations provide valuable genomic evolution. In E.coli, a DSB undergoes resection to give 3 ssDNA tails. These invading strand tails are loaded with RecA protein and then rapidly search the genome for the corresponding (allelic) partner. Thus, a searching ssDNA/RecA filament must almost never make stable non-allelic contact; therefore, it has been puzzling that RecA forms stable products that join partially homologous sequences. Homology testing by RecA family proteins begins with an 8-bp test, followed by successive homology tests of base pair triplets. Here we introduce a highly simplified homology recognition model to highlight how mismatch sensitivity could affect non-allelic pairing in bacterial genomes. The model predicts that even if each triplet test accepts 2 mismatches, RecA can have [~] 95% probability of establishing allelic pairing after a DSB in E. coli; however, that accuracy requires homology testing {gap}50 contiguous base pairs, consistent with the homology lengths probed in vivo. In contrast, if no mismatches are accepted testing 14 bp is sufficient, and testing more base pairs does not reduce non-allelic pairing because bacterial genomes contain long repeats.

biophysics↗

The sequences near Chi sites allow the RecBCD pathway to avoid genomic rearrangements

Bacterial recombinational repair is initiated by RecBCD, which creates a 3' single-stranded DNA (ssDNA) tail on each side of a double strand break (DSB). Each tail terminates in a Chi site sequence that is usually distant from the break. Once an ssDNA-RecA filament forms on a tail, the tail searches for homologous double-stranded DNA (dsDNA) to use as template for DSB repair. Here we show that the nucleoprotein filaments rarely trigger sufficient synthesis to form an irreversible repair unless a long strand exchange product forms at the 3' end of the filament. Our experimental data and modeling suggest that terminating both filaments with Chi sites allows recombinational repair to strongly suppress fatal genomic rearrangements resulting from mistakenly joining different copies of a repeated sequence after a DSB has occurred within a repeat. Taken together our evidence highlights cellular safe fail mechanisms that bacteria use to avoid potentially lethal situations.

biophysics↗