Proteins from the Fanconi anemia (FA) pathway play an integral role in DNA repair by homologous recombination (HR). FA is a multigenic disorder marked by progressive bone marrow failure and a strong cancer predisposition. Numerous studies have linked mutations in FA genes to familial breast, pancreatic, and other cancers, and have also provided ample evidence to implicate silencing of FA genes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNA damaging agents, DNA crosslinking chemicals and reactive aldehydes in particular, prone to DNA replicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem from defects in DNA damage signaling and repair, and FA protein functional and physical interactions have indicated an important link to the familial breast cancer proteins BRCA1 and BRCA2. The involvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscores the need to understand the mechanistic underpinnings of this genome maintenance pathway. In this project, we will employ a combination of biochemical and in vivo approaches to test the novel hypotheses that the FA pathway coordinates the prevention and resolution of genotoxic structures resulting from aberrant transcription events and HR.
Aim 1 will focus on the mechanism whereby the ID2 complex and UAF1-containing complexes engage nucleic acid containing structures and activate HR.
Aim 2 will explore how the FANCM-BLM axis resolves pathogenic RNA containing and other nucleic acid intermediates in a way that regulates HR activities. The success of this project is assured by the complementary expertise of the two participating Yale groups, led by Dr Patrick Sung and Dr Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yale community. In addition, the PIs have enlisted two investigators, Dr. Claudia Wiese and Dr. Andres Aguilera, whose expertise will even more elegantly allow the team to interrogate this novel area of genomic instability. These attributes help ensure that findings of the highest possible impact will be obtained. Since the biology of FA intersects with cancer biology in general, our project promises to shed light on critical processes of genomic surveillance as well as common themes of oncogenesis. We expect our studies to yield insight into common pathways of cancer and to identify novel targets for manipulation in cancer therapy.

Public Health Relevance

This MPI grant focuses on understanding the mechanistic underpinnings of the Fanconi anemia (FA) pathway of DNA damage response, needed for genome maintenance and general tumor suppression in humans. As a critical step toward accomplishing this objective, we outline multidisciplinary studies directed at delineating distinct stages of the FA pathways, using newly devised experimental systems that are ideally suited to testing disease causative mutations in FA proteins. The results from our joint venture should constitute the intellectual basis for devising strategies to advance cancer prevention, diagnosis, and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA168635-07
Application #
9878699
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Witkin, Keren L
Project Start
2019-01-01
Project End
2022-03-31
Budget Start
2019-01-01
Budget End
2019-03-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Rao, Timsi; Longerich, Simonne; Zhao, Weixing et al. (2018) Importance of homo-dimerization of Fanconi-associated nuclease 1 in DNA flap cleavage. DNA Repair (Amst) 64:53-58
Pires, Elena; Sung, Patrick; Wiese, Claudia (2017) Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis. DNA Repair (Amst) 59:76-81
Zhao, Weixing; Steinfeld, Justin B; Liang, Fengshan et al. (2017) BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550:360-365
Xu, Jingfei; Zhao, Lingyun; Xu, Yuanyuan et al. (2017) Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange. Nat Struct Mol Biol 24:40-46
Chen, X; Bosques, L; Sung, P et al. (2016) A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage. Oncogene 35:22-34
Liang, Fengshan; Longerich, Simonne; Miller, Adam S et al. (2016) Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex. Cell Rep 15:2118-2126
Zhao, Weixing; Vaithiyalingam, Sivaraja; San Filippo, Joseph et al. (2015) Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry. Mol Cell 59:176-87
Gaines, William A; Godin, Stephen K; Kabbinavar, Faiz F et al. (2015) Promotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52. Nat Commun 6:7834
Zhao, Weixing; Sung, Patrick (2015) Significance of ligand interactions involving Hop2-Mnd1 and the RAD51 and DMC1 recombinases in homologous DNA repair and XX ovarian dysgenesis. Nucleic Acids Res 43:4055-66
Parplys, Ann C; Zhao, Weixing; Sharma, Neelam et al. (2015) NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability. Nucleic Acids Res 43:9817-34

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