PALB2 is tumor suppressor protein that physically and functionally links BRCA1 and BRCA2, the two major breast cancer suppressors. The 3 proteins form a BRCA complex and function together in DNA double strand break (DSB) repair and cell cycle checkpoint control following DNA damage. These functions are critical for the maintenance of genome stability and suppressing tumorigenesis. We and others have shown that BRCA1 functions upstream of PALB2 and BRCA2. However, how BRCA1 regulates PALB2 in various DSB repair pathways remain poorly understood, and the mechanism how the 3 proteins promote checkpoint response remains unknown. Moreover, how much of BRCA1's tumor suppressive function is transmitted by PALB2 and to what extent PALB2's in vivo function depends on BRCA1 are also unknown. In this project, we will delve into the molecular underpinnings of the BRCA1- PALB2-BRCA2 DNA damage response network to understand key regulatory mechanisms that govern DSB repair efficiency, pathway choice and checkpoint control. Moreover, we will also use our newly generated Palb2 knockin mouse, in which the endogenous PALB2 is unable to bind BRCA1, to explore the etiology and tissue specificity of PALB2- and BRCA1-associated cancers.
In Aim1, we will investigate the role and mechanism of the BRCA1-PALB2 interaction in homologous recombination (HR) and single strand annealing (SSA).
In Aim2, we will define the mechanism of BRCA1, PALB2 and BRCA2 in the G2/M checkpoint control.
In Aim3, we will use the above mouse model to explore the role of the BRCA1-PALB2 complex formation in the DNA damage response in vivo and in tumor suppression in different tissues.

Public Health Relevance

By defining the mechanisms of the BRCA1-PALB2-BRCA2 pathway in the DNA damage response and tissue-specific tumor suppression, this study will advance our understanding of hereditary breast cancer development and tumor cell vulnerabilities. Results from this study may provide a scientific basis and preclinical reference for the rational design of novel approaches for the prevention and better treatment of the cancers. Insights from this study may also apply to other, hereditary or sporadic cancers associated with DNA damage, and therefore have broader implications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138804-10
Application #
9706732
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Witkin, Keren L
Project Start
2009-07-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rbhs -Cancer Institute of New Jersey
Department
Type
Overall Medical
DUNS #
078728091
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Simhadri, Srilatha; Vincelli, Gabriele; Huo, Yanying et al. (2018) PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene :
Mahdi, Amar Hekmat; Huo, Yanying; Tan, Yongmei et al. (2018) Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-?B in Mice with Disengaged BRCA1-PALB2 Interaction. Cancer Res 78:3969-3981
Lu, Kevin; Alcivar, Allen L; Ma, Jianglin et al. (2017) NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction. Cancer Res 77:2881-2892
Foo, T K; Tischkowitz, M; Simhadri, S et al. (2017) Compromised BRCA1-PALB2 interaction is associated with breast cancer risk. Oncogene 36:4161-4170
Ginjala, Vasudeva; Rodriguez-Colon, Lizahira; Ganguly, Bratati et al. (2017) Protein-lysine methyltransferases G9a and GLP1 promote responses to DNA damage. Sci Rep 7:16613
Droz-Rosario, Roberto; Lu, Huimei; Liu, Jingmei et al. (2017) Roles of BCCIP deficiency in mammary tumorigenesis. Breast Cancer Res 19:115
Buisson, Rémi; Niraj, Joshi; Rodrigue, Amélie et al. (2017) Coupling of Homologous Recombination and the Checkpoint by ATR. Mol Cell 65:336-346
Anantha, Rachel W; Simhadri, Srilatha; Foo, Tzeh Keong et al. (2017) Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance. Elife 6:
Wu, Qian; Paul, Atanu; Su, Dan et al. (2016) Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites. Mol Cell 61:434-448
Cicchini, Michelle; Karantza, Vassiliki; Xia, Bing (2015) Molecular pathways: autophagy in cancer--a matter of timing and context. Clin Cancer Res 21:498-504

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