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BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage
The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resistant DNA synthesis (RDS) phenotype, however the mechanism has remained elusive. Here we show that cells without BRCA2 are unable to sufficiently restrain DNA replication fork progression after DNA damage, and the underrestrained fork progression is due primarily to Primase-Polymerase (PRIMPOL)-mediated repriming of DNA synthesis downstream of lesions, leaving behind single-stranded DNA gaps. Moreover, we find that BRCA2 associates with the essential DNA replication factor MCM10 and this association suppresses PRIMPOL-mediated repriming and ssDNA gap formation, while having no impact on the stability of stalled replication forks. Our findings establish an important function for BRCA2, provide insights into replication fork control during the DNA damage response, and may have implications in tumor suppression and therapy response.
Tumor suppressor BRCA2 is known to stabilize and restart stalled DNA replication forks. Here the authors show that BRCA2 is recruited to the replication fork through its interaction with MCM10 and inhibits Primase-Polymerase-mediated repriming, lesion bypass and single strand DNA gap formation after DNA damage.
Journal Article
Herding Hemingway's cats : understanding how our genes work
The language of genes has become common parlance. We know they make your eyes blue, your hair curly or your nose straight. The media tells us that our genes control the risk of cancer, heart disease, alcoholism or Alzheimer's. The cost of DNA sequencing has plummeted from billions of pounds to a few hundred, and gene-based advances in medicine hold huge promise. We've all heard of genes, but how do they actually work? Drawing on stories ranging from six toed cats and stickleback hips to Mickey Mouse mice and zombie genes - told by researchers working at the cutting edge of genetics - Kat Arney explores the mysteries in our genomes with clarity, flair and wit, creating a companion reader to the book of life itself.
Book
Structural basis for Polθ-helicase DNA binding and microhomology-mediated end-joining
DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) in complex with DNA containing different 3′-ssDNA overhangs. The structures reveal the sequential conformations adopted by Polθ-hel during the critical phases of DNA binding, microhomology searching, and microhomology annealing. The stepwise conformational changes within the Polθ-hel subdomains and its functional dimeric state are pivotal for aligning the 3′-ssDNA overhangs, facilitating the microhomology search and subsequent annealing necessary for DSB repair via MMEJ. Our findings illustrate the essential molecular switches within Polθ-hel that orchestrate the MMEJ process in DSB repair, laying the groundwork for the development of targeted therapies against the Polθ-hel.
DNA polymerase theta (Polθ) plays central roles in microhomology-mediated end joining (MMEJ) DNA damage repair. Here, the authors determine a series of structures of Polθ helicase domain during the MMEJ, revealing key conformational changes for DNA binding, microhomology search, and annealing.
Journal Article
DNA : the story of the genetic revolution
\"James D. Watson, the Nobel laureate whose pioneering work helped unlock the mystery of DNA's structure, charts the greatest scientific journey of our time, from the discovery of the double helix to today's controversies to what the future may hold. [This edition has been] updated to include new findings in gene editing, epigenetics, agricultural chemistry, as well as two entirely new chapters on personal genomics and cancer research\"--Provided by publisher.
BOOK
Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ
Non-homologous end joining (NHEJ) is the main repair pathway for double-strand DNA breaks (DSBs) in mammals. DNA polymerases lambda (Pol λ) and mu (Pol μ), members of the Pol X family, play a key role in this process. However, their interaction within the NHEJ complexes is unclear. Here, we present cryo-EM structures of Pol λ in complex with the DNA-PK long-range synaptic complex, and Pol μ bound to Ku70/80-DNA. These structures identify interaction sites between Ku70/80 and Pol X BRCT domains. Using mutants at the proteins interface in functional assays including cell transfection with an original gap-filling reporter, we define the role of the BRCT domain in the recruitment and activity of the two Pol X members in NHEJ and in their contribution to cell survival following DSBs. Finally, we propose a unified model for the interaction of all Pol X members with Ku70/80.
The molecular basis for the enrollment of X family DNA polymerases in non-homologous end joining (NHEJ) is unclear. Here the authors elucidate the structure of Pol λ within the DNA-PK long-range complex and Pol μ in association with Ku70/80 and characterize the interaction between the BRCT domains of Pol λ and μ with Ku70/80.
Journal Article
Structural basis for intrinsic strand displacement activity of mitochondrial DNA polymerase
Members of the Pol A family of DNA polymerases, found across all domains of life, utilize various strategies for DNA strand separation during replication. In higher eukaryotes, mitochondrial DNA polymerase γ relies on the replicative helicase TWINKLE, whereas the yeast ortholog, Mip1, can unwind DNA independently. Using Mip1 as a model, we present a series of high-resolution cryo-EM structures that capture the process of DNA strand displacement. Our data reveal previously unidentified structural elements that facilitate the unwinding of the downstream DNA duplex. Yeast cells harboring Mip1 variants defective in strand displacement exhibit impaired oxidative phosphorylation and loss of mtDNA, corroborating the structural observations. This study provides a molecular basis for the intrinsic strand displacement activity of Mip1 and illuminates the distinct unwinding mechanisms utilized by Pol A family DNA polymerases.
Mitochondrial DNA polymerases use different mechanisms for strand separation during replication. Here, the authors reveal the cryo-EM structures of yeast Mip1, identifying key structural elements that enable strand displacement. Mutations in these elements impair mitochondrial function and DNA maintenance.
Journal Article
DNA testing and privacy
\"Home DNA testing companies, such as 23 and Me and AncestryDNA, are at peak popularity, fulfilling our desires to know where we come from and what our future might look like. But questions have arisen about who owns test results and whether testing companies have the right to sell customers' data to pharmaceutical companies and other outlets. Yet home DNA tests have been credited with catching criminals, such as the Golden State Killer. Containing viewpoints from diverse voices in the field, this volume examines the controversies surrounding home DNA tests.\"-- Provided by publisher.
Book
Strand-resolved mutagenicity of DNA damage and repair
DNA base damage is a major source of oncogenic mutations
1
. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation
2
. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication
3
,
4
, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts
5
. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.
How strand-asymmetric processes such as replication and transcription interact with DNA damage to drive mechanisms of repair and mutagenesis is explored.
Journal Article