Ionizing radiation (IR) is an important therapeutic approach to kill cancer cells by inducing DNA double strand breaks (DSBs) that lead to cell apoptosis. However, normal cells are protected from IR-induced cell lethality by a DNA damage response system including DNA damage checkpoint activation and DNA damage repair. Thus, it is important for understanding the molecular mechanism of IR-induced DNA damage response, so that more effective radiation therapy can be achieved to treat cancer patients. In response to IR-induced DSBs, a signal cascade initiated by a group of PI3-like kinases including ATM, ATR and DNAPK arrests cell cycle progression and facilitates DNA damage repair. Besides these protein phosphorylation events, we and others recently found that a protein ubiquitination cascade is involved in DSBs response. These ubiquitination events are activated by RNF8, a Ring domain E3 ligase. Following the initial RNF8-dependent ubiquitination, the ubiquitin (ub) signals are amplified by a group of downstream ub E3 ligases, such as RNF168, RNF169, RAD18, and HERC2. These ubiquitination events regulate chromatin remodeling and other histone marks, which facilitates DNA damage repair by recruiting down-stream DNA damage repair factors to DSBs. In this application, we plan to continue studying the IR-induced protein ubiquitination cascade by focusing on CHFR, a paralog of RNF8 in mammals. The domain architecture of CHFR and RNF8 is very similar. Both of them contain an N-terminal FHA domain that is likely to recognize phospho-Thr, and a Ring domain that interacts Ubc13 or UbcH5C to catalyze histone ubiquitination in response to DSBs. Lacking these two E3 ub ligases additively suppress DNA damage response and induces tumorigenesis in vivo. Different from RNF8, CHFR contains a C-terminal PBZ motif that binds poly(ADP-ribose) (PAR), which facilitates the fast recruitment of CHFR to DNA damage sites and mediates the ubiquitinaition of PARP1. Moreover, Chfr-deficient mice are tumor prone, and cancer-associated CHFR gene mutations have been identified in primary solid tumors. These lines of evidence suggest that CHFR is an important tumor suppressor. Thus, in this application, we plan to examine the molecular mechanism of CHFR in IR-induced DNA damage response and tumor suppression.

Public Health Relevance

Dysfunction of ionizing radiation-induced DNA damage response pathways causes a great risk to induce tumorigenesis. In our preliminary study, we identified an important regulator - CHFR in the ionizing radiation - induced DNA damage response. In this proposal, we plan to not only dissect the molecular mechanism of CHFR underlining ionizing radiation-induced DNA damage response, but also examine the role of CHFR in tumor suppression in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA130899-06A1
Application #
8757646
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2007-12-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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