Double-Strand Break Repair Independent Role For BRCA2 In Blocking Stalled Replication Fork Degradation By MRE11

By K. Schlacher, N. Christ, Nicolas Siaud, A. Egashira, Hong Wu, M. Jasin. Cell, 2011

1,241 citations recorded by the source corpus.

SUMMARY Breast cancer suppressor BRCA2 is critical for maintenance of genomic integrity and resistance to agents that damage DNA or collapse replication forks, presumably through homology-directed repair of double-strand breaks (HDR). Using single-molecule DNA fiber analysis, we show here that nascent replication tracts created before fork stalling with hydroxyurea are degraded in the absence of BRCA2 but are stable in wild-type cells. BRCA2 mutational analysis reveals that a conserved C-terminal site, involved in stabilizing RAD51 filaments but not in loading RAD51 onto DNA, is essential for this fork protection but dispensable for HDR. RAD51 filament disruption in wild-type cells phenocopies BRCA2 deficiency. BRCA2 prevents chromosomal aberrations upon replication stalling, which are alleviated by inhibition of MRE11, the nuclease responsible for this novel fork instability. Thus, BRCA2 prevents rather than repairs nucleolytic lesions at stalled replication forks to maintain genomic integrity, and hence likely suppresses tumorigenesis through this novel replication-specific function.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/922b998739a0bfe97e1d23ff8409cde299ef1d3d

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In Molecular Biology

1. Thomas Helleday
2. Weiran Feng
3. Yu Zhang
4. Rohit Prakash
5. Xiaolan Zhao
6. L. Krejci
7. M. Jasin
8. M. Špírek

In Plant Science

1. M. Jasin

Citations in the corpus

• A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2 (2012, methodology): “Specifically, nascent replication tracts were IdU-labeled before replication stalling with hydroxyurea (HU) (Figure 1B); the retention of the label after HU treatment serves as a measure for fork stability using DNA fiber spreading (Schlacher et al., 2011).”
• Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Recent work has provided evidence that this function is achieved through a RAD51-dependent, but HR-repair-independent mechanism, such that BRCA2 protects nascent DNA strand from degradation by stabilizing the RAD51 filament to maintain genomic integrity under replication stress (Schlacher et al. 201”
• BRCA1 and BRCA2: different roles in a common pathway of genome protection (2011, background): “HR appears to be the major mechanism for protecting the integrity of the genome in proliferating cells, because other DSB repair pathways are error-prone and generate chromosome deletions and translocation”
• The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings (2011, background): “Interestingly, a recent publication demonstrates that BRCA2 protects from Mre11-depedent degradation of stalled replication forks, a function unrelated to HR (Schlacher et al., 2011).”
• Homologous recombination and its regulation (2012, background): “In another case, the C-terminal domain of BRCA2 is essential for fork protection by stabilizing RAD51 filaments and preventing MRE11mediated degradation (191).”