DNA repair machines are at the center of what leads to cancer-causing mutations, what prevents cancer, what interferes with cancer treatment, and what is the Achilles heel for cancer-targeted treatment. For NCI, SBDR coordinates leaders in DNA repair (DR) to work together synergistically to provide a comprehensive, mechanistic understanding of DR processes. SBDR removes bottlenecks within individual laboratories and promotes the concerted efforts of multidisciplinary researchers with expertise in different facets of DR. The SBDR Projects and Cores together enable a comprehensive cross-pathway knowledge of dynamic multi- functional DR machines ? an understanding that can only be achieved through multi-disciplinary approaches and concerted efforts by multiple groups. The goals of SBDR are 1) to develop structure-based, mechanistic foundation for an actionable understanding of dynamic, multi-functional DR molecular complexes suitable for cancer biology, prognosis, and predispositions, and 2) to enable an integrated quantitative and mechanistic knowledge of DR machines, pathways, and intersections with replication and apoptosis sufficient to aid prediction and intervention for cancer biology by bridging the gaps from mutant sequences to system level correlation. By integrating analyses of major DR and damage response pathways with replication, SBDR will provide detailed and comprehensive information on the maintenance of genetic integrity spanning from specific proteins and complexes to pathways, networks, and signaling. We will apply knowledge-based, determination and integration of structural, biochemical, and biological data on DR protein interactions, modifications, and complexes acting in the five Projects. Our multifaceted structure-based strategy is needed both to dissect multiple activities of multi-functional complexes, such as Mre11-Rad50-Nbs1, and to define how proteins act in multiple pathways. In concert, SBDR Projects and Cores will accomplish four Program Aims: 1) Determine definitive and biologically validated structures of DR complexes, interfaces, & conformations; 2) Dissect the multi-functionality of DR machineries tested by structurally-based examination of separation-of-function mutations and chemical inhibitors; 3) Define crosstalk for DR pathway interactions and delineate and test how DR pathway choice is made; and 4) Discover synthetic lethalities brought about by either mutations or chemical agents that target a specific DR activity that is lethal only in the context of another DR defect to identify and test specific ways to intervene and control biological outcomes to DNA damage for cancer interventions. SBDR will inform cancer biology by providing a comprehensive mechanistic knowledge of how cells respond to DNA damage and how multi-functional DR proteins act in the context of other DNA processes. SBDR will advance understanding of how DR mutations may differentially impact cancer susceptibility and patient risk. SBDR will aid research employing Cancer Genome Atlas mutations and system level correlations as well as consequent therapeutic strategies by providing mechanistic and predictive insights.
DNA repair is an essential component to understanding and treating cancer. Mutations in DNA repair lead to the initiation of cancer, DNA repair can work antagonistically against cancer treatments that damage DNA, and importantly, known mutations of DNA repair in specific cancer cells can provide an opportunity to develop effective treatment. SBDR brings together the top laboratories in DNA repair through multi-disciplinary collaborations to define the complex and dynamic network of DNA repair machines. The goal is to develop an actionable, quantitative and mechanistic knowledge of DNA repair machines, pathways and intersections with other DNA processes to aid prediction and intervention for cancer biology.
|Sung, Patrick (2018) Introduction to the Thematic Minireview Series: DNA double-strand break repair and pathway choice. J Biol Chem 293:10500-10501|
|Shen, Jianfeng; Ju, Zhenlin; Zhao, Wei et al. (2018) ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 24:556-562|
|Sengupta, Shiladitya; Yang, Chunying; Hegde, Muralidhar L et al. (2018) Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress. DNA Repair (Amst) 66-67:1-10|
|Mu, Hong; Geacintov, Nicholas E; Broyde, Suse et al. (2018) Molecular basis for damage recognition and verification by XPC-RAD23B and TFIIH in nucleotide excision repair. DNA Repair (Amst) :|
|Chavez, Diana A; Greer, Briana H; Eichman, Brandt F (2018) The HIRAN domain of helicase-like transcription factor positions the DNA translocase motor to drive efficient DNA fork regression. J Biol Chem 293:8484-8494|
|Wang, Jing L; Duboc, Camille; Wu, Qian et al. (2018) Dissection of DNA double-strand-break repair using novel single-molecule forceps. Nat Struct Mol Biol 25:482-487|
|Crickard, J Brooks; Kaniecki, Kyle; Kwon, Youngho et al. (2018) Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase. Proc Natl Acad Sci U S A 115:E10041-E10048|
|Syed, Aleem; Tainer, John A (2018) The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair. Annu Rev Biochem 87:263-294|
|Howes, Timothy R L; Sallmyr, Annahita; Brooks, Rhys et al. (2018) Erratum to ""Structure-activity relationships among DNA ligase inhibitors; characterization of a selective uncompetitive DNA ligase I inhibitor"" [DNA Repair 60C (2017) 29-39]. DNA Repair (Amst) 61:99|
|Bhattacharyya, Sudipta; Soniat, Michael M; Walker, David et al. (2018) Phage Mu Gam protein promotes NHEJ in concert with Escherichia coli ligase. Proc Natl Acad Sci U S A 115:E11614-E11622|
Showing the most recent 10 out of 484 publications