Chromatin modifications profoundly influence DNA repair, tumor suppression, and response to chemotherapy. A powerful genetic interaction between chromatin associated DNA repair proteins BRCA1 and 53BP1 exemplifies the importance of chromatin recognition to these phenomena. Heterozygous BRCA1 mutation confers a high risk of breast and ovarian cancer. BRCA1 mutant tumors lose the wildtype allele, rendering them effectively BRCA1 null. Consequently, BRCA1 mutant cancers respond clinically to poly(ADP)ribose polymerase inhibitors (PARPi) due to severely impaired homologous recombination (HR) mediated DNA repair. Impaired HR also underlies the embryonic lethality in BRCA1 knockout mice due to massive genomic instability. Strikingly, double null BRCA1-/-, 53BP1-/- mice survive to adulthood without increased cancer incidence, and show an order of magnitude less radial chromosome formation in response to PARPi than do BRCA1-/-, 53BP1+/+ cells. This remarkable genetic rescue occurs because 53BP1 deficiency restores HR in BRCA1 mutant cells, suggesting that inappropriate 53BP1 activity is causative for genomic instability and cancer formation in BRCA1 mutant cells. It is therefore of central importance to understand the molecular determinants that differentially control BRCA1 and 53BP1 DNA repair functions. We present evidence that histone acetylation is a critical determinant of a competition between BRCA1 and 53BP1 for accumulation at chromatin adjacent to DNA double strand breaks (DSBs). These findings support a model whereby sequential histone H4 tail acetylation and methylation regulate DNA repair mechanism utilization by segregating BRCA1 and 53BP1 to different chromatin territories adjacent to DSBs. We will investigate the molecular basi underlying these observations and seek to understand the relationship between chromatin structure and basic DNA repair mechanisms that influence responses to clinically important chemotherapeutic agents.

Public Health Relevance

A powerful genetic interaction between chromatin associated BRCA1 and 53BP1 exemplifies the importance of chromatin recognition to DNA repair, tumor suppression, and response to chemotherapy. BRCA1-/-, 53BP1-/- mice survive to adulthood without increased cancer incidence, and show an order of magnitude less radial chromosome formation in response to PARPi than do BRCA1-/-, 53BP1+/+ cells. This remarkable genetic rescue occurs because 53BP1 deficiency restores HR in BRCA1 mutant cells. It is therefore of central importance to understand the molecular determinants that differentially control BRCA1 and 53BP1 DNA repair functions.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA174904-02
Application #
8623113
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sawyer, Sarah L; Tian, Lei; Kähkönen, Marketta et al. (2015) Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov 5:135-42
Cho, Nam Woo; Dilley, Robert L; Lampson, Michael A et al. (2014) Interchromosomal homology searches drive directional ALT telomere movement and synapsis. Cell 159:108-21
Li, Mischa L; Yuan, Gang; Greenberg, Roger A (2014) Chromatin yo-yo: expansion and condensation during DNA repair. Trends Cell Biol 24:616-8
Hendzel, Michael J; Greenberg, Roger A (2013) Conversations between chromatin modifications and DNA double strand break repair: a commentary. Mutat Res 750:1-4
Shanbhag, Niraj M; Greenberg, Roger A (2013) The dynamics of DNA damage repair and transcription. Methods Mol Biol 1042:227-35
Zheng, Hui; Gupta, Vibhor; Patterson-Fortin, Jeffrey et al. (2013) A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep 5:180-93