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Human BRCA2 protects the DNA when replication forks stall, whereas MRE11-RAD50 and WRN-DNA2 process or partially degrade these substrates. When mutated, these genes result in distinct genetic instabilities and cancers, arguing they have unique, not redundant, functions. Escherichia coli encodes functional homologs of MRE11-RAD50 (SbcC-SbcD), WRN-DNA2 (RecQ-RecJ), and BRCA2 (RecF). Here, we use 2-dimensional gels, pulse-labelling, and replication-profiling analysis to show the bacterial homologs act at distinct substrates and loci on the chromosome. Whereas RecF and RecJ-RecQ protect and process DNA at arrested replication forks to facilitate repair, RecBCD and SbcC-SbcD protect and process DNA at sites where forks converge. Comparing the assays used in E. coli to human cells, we consider whether these cellular roles may be functionally conserved.
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Recombination Mediator Proteins: Misnomers That Are Key to Understanding the Genomic Instabilities in Cancer
Recombination mediator proteins have come into focus as promising targets for cancer therapy, with synthetic lethal approaches now clinically validated by the efficacy of PARP inhibitors in treating BRCA2 cancers and RECQ inhibitors in treating cancers with microsatellite instabilities. Thus, understanding the cellular role of recombination mediators is critically important, both to improve current therapies and develop new ones that target these pathways. Our mechanistic understanding of BRCA2 and RECQ began in Escherichia coli. Here, we review the cellular roles of RecF and RecQ, often considered functional homologs of these proteins in bacteria. Although these proteins were originally isolated as genes that were required during replication in sexual cell cycles that produce recombinant products, we now know that their function is similarly required during replication in asexual or mitotic-like cell cycles, where recombination is detrimental and generally not observed. Cells mutated in these gene products are unable to protect and process replication forks blocked at DNA damage, resulting in high rates of cell lethality and recombination events that compromise genome integrity during replication.
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- Award ID(s):
- 1916625
- PAR ID:
- 10339527
- Date Published:
- Journal Name:
- Genes
- Volume:
- 13
- Issue:
- 3
- ISSN:
- 2073-4425
- Page Range / eLocation ID:
- 437
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/genes13030437
