The Mutational Landscape of Cancer's Vulnerability to Ionizing Radiation.

Purpose: Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown.

Experimental Design: We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells.

Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation.

Targeted α-particle-emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to α-particle irradiation could guide and accelerate clinical translation. Here, we performed high-content profiling of cellular survival following exposure to α-particles emitted from radium-223 (Ra) using 28 genetically diverse human tumor cell lines.

Homologous Recombination-Mediated DNA Repair and Implications for Clinical Treatment of Repair Defective Cancers.

Double-strand DNA breaks (DSBs) are generated by ionizing radiation and as intermediates during the processing of DNA, such as repair of interstrand cross-links and collapsed replication forks. These potentially deleterious DSBs are repaired primarily by the homologous recombination (HR) and nonhomologous end joining (NHEJ) DNA repair pathways. HR utilizes a homologous template to accurately restore damaged DNA, whereas NHEJ utilizes microhomology to join breaks in close proximity.

RNF138 interacts with RAD51D and is required for DNA interstrand crosslink repair and maintaining chromosome integrity.

The RAD51 family is integral for homologous recombination (HR) mediated DNA repair and maintaining chromosome integrity. RAD51D, the fourth member of the family, is a known ovarian cancer susceptibility gene and required for the repair of interstrand crosslink DNA damage and preserving chromosomal stability. In this report, we describe the RNF138 E3 ubiquitin ligase that interacts with and ubiquitinates the RAD51D HR protein.

A genetic basis for the variation in the vulnerability of cancer to DNA damage.

Radiotherapy is not currently informed by the genetic composition of an individual patient's tumour. To identify genetic features regulating survival after DNA damage, here we conduct large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 533 genetically annotated human tumour cell lines. We show that sensitivity to radiation is characterized by significant variation across and within lineages.

Functional characterization and identification of mouse Rad51d splice variants.

Background: The homologous recombination (HR) pathway is vital for maintaining genomic integrity through the restoration of double-stranded breaks and interstrand crosslinks. The RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) are essential for this process in vertebrates, and the RAD51D paralog is unique in that it participates in both HR repair and telomere maintenance. RAD51D is also known to directly interact with the RAD51C and XRCC2 proteins.